CN115703770A - Pyrimidinamine compound and composition and application thereof - Google Patents
Pyrimidinamine compound and composition and application thereof Download PDFInfo
- Publication number
- CN115703770A CN115703770A CN202210951339.4A CN202210951339A CN115703770A CN 115703770 A CN115703770 A CN 115703770A CN 202210951339 A CN202210951339 A CN 202210951339A CN 115703770 A CN115703770 A CN 115703770A
- Authority
- CN
- China
- Prior art keywords
- radical
- alkyl
- chloro
- heteroaryl
- ethoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention provides a pyrimidinamine compound shown as a formula (I), or a stereoisomer, a tautomer, a nitric oxide, a solvate or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition in preparation of medicines for preventing, treating and/or relieving PI 3-kinase isokinaseA commonly associated disease, disorder, and/or condition, or a medicament that inhibits PI 3-kinase activity. The compound provided by the invention shows excellent inhibitory activity and kinase selectivity on PI 3-kinase.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a novel pyrimidinamine compound, a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition in preparation of medicines for preventing, treating and/or relieving diseases, disorders and/or conditions related to PI 3-kinase abnormity.
Background
The phosphoinositide 3-kinase (PI 3K) pathway is an intracellular signaling pathway that has a regulatory role in cell survival, proliferation and differentiation. The phosphoinositide 3-kinase (PI 3K) enzyme family is a central regulator of growth, proliferation, migration and metabolism in many cells and tissues. PI3K is a lipid kinase that produces lipid second messenger phosphatidylinositol-3,4,5-triphosphate (PIP 3), which is used downstream of cell surface receptors to regulate growth, metabolism, survival and differentiation. PIP3 is produced by four different class I PI3K catalytic isomers, divided into two groups: class IA (p 110 α, p110 β, and p110 δ) and class IB (p 110 γ). All class I PI3ks are constitutively associated with regulatory subunits, and the main difference between class IA and class IB PI3ks is that they are associated with unique regulatory subunits. In normal cells, the PI3K/mTOR pathway has a regulatory role in cell survival, proliferation, and differentiation. However, aberrant activation of this pathway has been implicated in a variety of human diseases, including cancer, immunodeficiency, inflammation, and developmental disorders. Multiple inhibitors directed against key nodes within the PI3K pathway are in different stages of clinical development for the treatment of a variety of human diseases. ("Small-molecular inhibitors of the PI3K signaling network," Future MedChem.2011,3 (5), 549-565).
PI3Ks can be divided into three classes (I, II and III) based on differences in gene sequence, structure, adaptor molecules, expression, activation mechanisms and substrates. Among them, the class I PI3ks can be classified into IA and IB according to signal pathways and regulatory proteins. Class IA PI3ks (PI 3K α, PI3K β and PI3K δ) are heterodimeric complexes consisting of a catalytic subunit p110 (p 110 α, p110 β and p110 δ, respectively) and a regulatory subunit p85 (e.g., p85 α, p85 β, p55 δ, p55 α and p50 α). These signal responses are typically transmitted via Receptor Tyrosine Kinases (RTKs). The class IB PI3K γ signal is transmitted via G protein-coupled receptors (GPCRs) and consists of the catalytic subunit p110 γ, and the regulatory subunit associated with p110 γ is distinct from the class IA subtype.
The expression patterns of both PI3K α and PI3K β subtypes are ubiquitous, while both PI3K δ and PI3K γ subtypes are mainly expressed in leukocytes. The relatively restricted expression patterns of PI3K δ and PI3K γ suggest an important role for these two subtypes in the adaptive and innate immune systems (j.med. Chem.2012,55 (20), 8559-8581).
PI3K δ is essential for PI (3,4,5) P3 of CD28 to form downstream and/or T Cell Receptor (TCR) signals. An important role downstream of the PI3K signaling of TCRs is the activation of Akt, which phosphorylates anti-apoptotic factors as well as a number of different transcription factors for cytokine production. Thus, T cells with inactivated PI3K δ are deficient in proliferation and secretion of Th1 and Th2 cytokines. Activation of T cells by CD28 lowers the threshold for TCR activation by antigen and increases the magnitude and duration of the proliferative response. These effects are mediated by a delta-dependent increase in PI3K in the transcription of many genes, including IL2, an important T cell growth factor.
The role of PI3K δ in B cell proliferation, antibody secretion, B-cell antigen and IL-4 receptor signaling, B-cell antigen presentation function was also determined (j.immunol. (2007) 178 (4) p.2328-35 blood (2006) 107 (2) p.642-50) and demonstrated its role in autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. Therefore, PI3K inhibitors would also have a better therapeutic effect for the above indications.
The involvement of the activated PI3K pathway in the identification of hematological malignancies has led to a great deal of research in this area, and 3 PI3K inhibitors are currently approved by the U.S. food and drug administration for the treatment of Chronic lymphocytic leukemia (Chronic lymphocytic leukemia); follicular non-Hodgkin lymphoma (follicullar B-cell non-Hodgkin lymphoma) and Small lymphocytic lymphoma (Small lymphocytic lymphoma). Idelalisib (against the delta subtype) is the first approved PI3K inhibitor in the field, followed by copanlisib (a pan PI3K subtype inhibitor, acting mainly on alpha and delta), and more recently duvelisib (a PI3K gamma and delta inhibitor). The approval of these PI3K inhibitors is based on their activity in relapsed or refractory B cell malignancies after at least 2 previous treatments. Notably, PI3K inhibitors are targeted/immunomodulatory drugs, not cytotoxic chemotherapeutics, and their unique mechanism of action results in differential safety. Given the importance of the PI3K pathway in normal leukocyte function, inhibition of PI3K requires a key balance to be achieved between the effects of tumor microenvironment levels and protection of immune function. (Clinical Lymphoma, myeloma & Leukemia,2020, vol.21, no.1, 8-20).
There is a need to provide new PI3K inhibitors that are good drug candidates. In particular, preferred compounds should bind strongly to PI3K receptors while showing little affinity for other receptors. The compound should be well absorbed from the gastrointestinal tract, be metabolically stable and have good pharmacokinetic properties. When targeting receptors in the central nervous system, they are free to cross the blood brain barrier, and when selectively targeting receptors in the peripheral nervous system, they should not cross the blood brain barrier. They should be non-toxic and exhibit few side effects. In addition, the ideal drug candidate should exist in a physical form that is stable, non-hygroscopic, and easily formulated. The compounds of the invention show specific levels of selectivity for PI3K α, β, γ and δ against different paralogs. In particular, a certain level of selectivity against p Ι 3K δ was shown.
The compounds, compositions and methods described herein directly correspond to these needs and other objects. In particular, the invention provides a class of compounds that inhibit, modulate and/or regulate PI 3-kinase activity, for use in the treatment and/or prevention of diseases, disorders, and/or conditions associated with PI 3-kinase abnormalities. Compared with the existing similar compounds, the compound has better pharmacological activity, and particularly shows excellent inhibitory activity and kinase selectivity on PI 3-kinase. Therefore, the compound has very good development prospect.
Disclosure of Invention
Definition of terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, such as compounds of the general formula of the invention, or as specified in the examples, subclasses, and classes encompassed by the invention.
It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure is replaced with a particular substituent, whether the hydrogen atom is attached to a C or N atom or other atom. "optionally" unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.
The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including, but not limited to, H, D, oxo (= O), F, cl, br, I, -OH, -CN, -NO 2 、-NR e R f 、-C(＝O)R 9 、-OC(＝O)R 9 、-C(＝O)OR 9a 、-S(＝O) 0-2 R 9 、-OS(＝O) 1-2 R 9 、-S(＝O) 1-2 OR 9a 、-N(R 10a )C(＝O)R 10 、-C(＝O)NR 10a R 10 、-OC(＝O)NR 10a R 10 、-N(R 10a )S(＝O) 1-2 R 10 、-S(＝O) 1-2 NR 10a R 10 、-N(R 10a )C(＝O)NR 10a R 10 、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-7 Heterocyclic group, C 2-7 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 An alkyl group; wherein each substituent is independently optionally substituted with 0,1, 2,3, or 4 substituents independently selected from H, D, oxo (= O), F, cl, br, -OH, -NH 2 、-CN、-NO 2 、C 1-6 Alkyl and C 1-6 Alkoxy, and the like. Wherein R is e 、R f 、R 9 、R 9a 、R 10 And R 10a Have the definitions as described in the present invention.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C 1 -C 6 Alkyl "means in particular independently disclosed methyl, ethyl, C 3 Alkyl radical, C 4 Alkyl radical, C 5 Alkyl and C 6 An alkyl group.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described herein.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl group (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH)) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2,3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3,3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp 2 Double bonds, which include both "cis" and "trans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH = CH) 2 ) Allyl (-CH) 2 CH＝CH 2 ) And so on. The alkenyl group may be optionally substituted with one or more substituents described herein.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, the alkynyl group comprisesContaining 2 to 6 carbon atoms; in yet another embodiment, an alkynyl group contains 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C ≡ CH), propargyl (-CH) 2 C [ identical to ] CH), 1-propynyl (-C [ identical to ] C-CH) 3 ) And so on. The alkynyl group may be optionally substituted with one or more substituents described herein.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the definition as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentyloxy (n-pentyloxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyloxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyloxy (-OCH (CH)) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH)) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And so on.
The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl (-CF) 3 ) Trifluoromethoxy (-OCF) 3 ) Difluoroethyl (-CH) 2 CHF 2 ,-CF 2 CH 3 ,-CHFCH 2 F) Trifluoroethyl (-CH) 2 CF 3 ,-CF 2 CH 2 F,-CFHCHF 2 )、-CF(CH 3 ) 2 And the like.
The terms "hydroxyalkyl" or "hydroxy-substituted alkyl" and "hydroxyalkoxy" or "hydroxy-substituted alkoxy" respectively denote an alkyl or alkoxy group, optionally substituted with one or more hydroxy groups, wherein "hydroxyalkyl" and "hydroxyalkyl" may be used interchangeably, examples of which include, but are not limited to, hydroxymethyl (-CH) 2 OH), 2-hydroxyethyl (-CH) 2 CH 2 OH), 1-hydroxyethyl (-CH (OH) CH 3 ) 2-hydroxypropan-2-yl (-COH (CH) 3 ) 2 ) 2-hydroxy-2-methylpropyl (-CH) 2 COH(CH 3 ) 2 ) 3-hydroxypropyl (-CH) 2 CH 2 CH 2 OH), 2-hydroxypropyl (-CH) 2 CH(OH)CH 3 ) 2-hydroxy-2-methylpropyl (-CH) 2 CH(OH)(CH 3 )CH 3 ) Hydroxy methoxy (-OCH) 2 OH), and the like.
The term "cyano-substituted alkyl" or "cyanoalkyl" includes C substituted with one or more cyano groups 1-10 A straight or branched alkyl group. In some of these embodiments, cyanoalkyl is C substituted with one or more cyano groups 1-6 "lower cyanoalkyl", other embodiments are C substituted with one or more cyano groups 1-4 "lower cyanoalkyl", such examples include, but are not limited to, CNCH 2 -、CNCH 2 CH 2 -、CNCH 2 CH 2 CH 2 -、CNCH 2 CHCNCH 2 -and the like.
The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C 1-6 Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C 1-3 Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.
The term "aminoalkyl" includes C substituted with one or more amino groups 1-10 A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups 1-6 "lower aminoalkyl" and other examples are aminoalkyl which is C substituted with one or more amino groups 1-4 Examples of "lower aminoalkyl" radicals include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Bicyclic cycloalkyl groups include spirobicycloalkyl, fused bicycloalkyl and bridged bicycloalkyl groups. In some embodiments, cycloalkyl groups contain 3 to 12 carbon atoms; in other embodiments, cycloalkyl groups contain 3 to 10 carbon atoms; in other embodiments, cycloalkyl groups contain 3 to 8 carbon atoms; in other embodiments, cycloalkyl groups contain 3 to 7 carbon atoms; in other embodiments, cycloalkyl groups contain 3 to 6 carbon atoms; in still other embodiments, cycloalkyl is C 7 -C 12 Cycloalkyl group containing C 7 -C 12 Monocycloalkyl radical, C 7 -C 12 Bicycloalkyl (e.g. C) 7 -C 12 Spirobicycloalkyl radical, C 7 -C 12 Fused bicycloalkyl and C 7 -C 12 Bridged bicycloalkyl) or C 7 -C 12 A tricycloalkyl group. The cycloalkyl groups may independently be unsubstituted or substituted by one or moreSubstituted by the substituents described in the present invention. The term "monocyclic cycloalkyl" or "monocycloalkyl" denotes a cycloalkyl group of a monocyclic ring system, wherein the cycloalkyl group has the definitions as described above, and the monocyclic cycloalkyl group can independently be unsubstituted or substituted by one or more substituents described herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
The term "cycloalkylalkyl" includes cycloalkyl-substituted alkyl groups. In some embodiments, cycloalkylalkyl groups refer to "lower cycloalkylalkyl" groups, i.e., the cycloalkyl group is attached to C 1-6 On the alkyl group of (a). In other embodiments, cycloalkylalkyl groups refer to C-containing groups 1-3 The "phenylalkylene" of an alkyl group of (a). Specific examples thereof include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentylethyl, cyclohexylethyl, and the like. The cycloalkyl group on the cycloalkylalkyl group may be further substituted with one or more substituents described herein.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a mono-, bi-or tricyclic ring system containing 3 to 12 ring atoms which is mono-or polyvalent, saturated or partially unsaturated, and which is not aromatic, wherein at least one ring atom is selected from nitrogen, oxygen and sulfur atoms. In some embodiments, heterocyclyl or heterocyclic ring contains 4-12 ring atoms. In some embodiments, heterocyclyl or heterocyclic contains 5-12 ring atoms. In some embodiments, heterocyclyl or heterocyclic ring contains 4-8 ring atoms. In some embodiments, heterocyclyl or heterocyclic contains 3-10 ring atoms. In some embodiments, heterocyclyl or heterocyclic contains 3-8 ring atoms. In some embodiments, heterocyclyl or heterocyclic contains 3-6 ring atoms. In some embodiments, heterocyclyl or heterocyclic contains 4-7 ring atoms. Unless otherwise specified, heterocyclyl groups may be carbonRadical or nitrogen radical, and-CH 2 The group can optionally be replaced by-C (= O) -the sulphur atom of the ring can optionally be oxidized to S-oxide and the nitrogen atom of the ring can optionally be oxidized to N-oxygen compound. The heterocyclic group includes a saturated heterocyclic group (heterocycloalkyl group) and a partially unsaturated heterocyclic group. The heterocyclic group has one or more attachment points to the rest of the molecule. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, azacycloheptyl, oxazepanyl, thiazepanyl, and the like
Radicals (e.g., 1,4-oxaza)
Mesityl, 1,2-oxaza
Alkyl), diazepine
Radicals (e.g. 1,4-diazepine)
Mesityl, 1,2-diazepine
Basic), dioxa
Radicals (e.g., 1,4-dioxa)
Mesityl, 1,2-dioxa
Basic), a sulfur aza
Radical (e.g. 1,4-thiazepine)
Mesityl, 1,2-thiazas
Indolyl), 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, 2-azaspiro [4.4]Nonanyl, 1,6-dioxaspiro [4.4 ]]Nonanyl, 2-azaspiro [4.5 ]]Decyl, 8-azaspiro [4.5 ]]Decyl, 7-azaspiro [4.5 ]]Decyl, 3-azaspiro [5.5 ]]Undecyl, 2-azaspiro [5.5]Undecyl, octahydro-1H-isoindolyl, octahydrocyclopenta [ c]Pyrrolyl, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, hexahydrofuro [3,2-b]Furyl and dodecahydroisoquinolinyl, and the like. Examples of substitutions of the-CH 2-group in a heterocyclyl by-C (= O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl and 3,5-dioxopiperidinyl. Examples of sulfur atoms in heterocyclic groups that are oxidized include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
In yet another embodiment, heterocyclyl is a 4-7 atom heterocyclyl and refers to a monovalent or polyvalent, saturated or partially unsaturated, nonaromatic, monocyclic or bicyclic ring of 4-7 ring atoms wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise specified, a heterocyclic group of 4 to 7 atoms may be carbon-based or nitrogen-based, and-CH 2 The-group may optionally be replaced by-C (= O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may beTo be optionally oxidized to the N-oxygen compound. The 4-7 atom heterocyclyl group has one or more attachment points to the rest of the molecule. Among them, examples of the monocyclic heterocyclic group consisting of 4 to 7 atoms include, but are not limited to: <xnotran> , , , , , , , , , , , , , , , 2H- , 4H- , , , , , , , , , 5363 zxft 5363- , 3242 zxft 3242- , , , , , , </xnotran>
Radical (1,4-oxaza)
Mesityl, 1,2-oxaza
Alkyl), diazepine
Radical (1,4-diazepine)
Mesityl, 1,2-diazepine
Alkyl) and thiazepine
Radical (1,4-thiazepine)
Mesityl, 1,2-thiazas
Base), etc.; examples of bicyclic heterocyclic groups consisting of 4 to 7 atoms include, but are not limited to: 3-azabicyclo [3,2,0]Heptane, 3-oxobicyclo [3,2,0]Heptane and the like; 4-7 atoms in heterocyclic radical 2 Examples of-groups substituted with-C (= O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl and 3,5-dioxopiperidinyl; examples of sulfur atoms in a 4-7 atom heterocyclic group that are oxidized include, but are not limited to, sulfolane, 1,1-dioxotetrahydrothiophene, 1,1-dioxotetrahydrothiopyran, 1,1-dioxothiomorpholinyl. Said heterocyclyl group of 4 to 7 atoms may be optionally substituted by one or more substituents as described herein.
The term "heterocyclylalkyl" includes heterocyclyl-substituted alkyl groups in which both the heterocyclyl and alkyl groups have the meaning as described herein, and such examples include, but are not limited to, tetrahydrofuryl-methyl, pyrrol-2-ylmethyl, morpholin-4-ylethyl, piperazin-4-ylethyl, piperidin-4-ylethyl, and the like.
The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms in the ring and one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may independently be optionally substituted with one or more substituents described herein.
The term "arylalkyl" or "aralkyl" includes aryl-substituted alkyl groups. In some embodiments, an arylalkyl group refers to a "lower arylalkyl" group, i.e., the aryl group is attached to C 1-6 On the alkyl group of (a). In other embodiments, arylalkyl group refers to a C-containing group 1-3 The "phenylalkylene" of an alkyl group of (a). Specific examples thereof include, but are not limited to, benzyl, diphenylmethyl, phenylethyl, and the like. The aryl group on the arylalkyl group may be further substituted with one or moreSubstituted by the substituents described in the present invention.
The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one aromatic ring contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In one embodiment, heteroaryl is a heteroaryl consisting of 5 to 12 atoms containing 1,2,3 or 4 heteroatoms independently selected from O, S and N. In another embodiment, heteroaryl is a heteroaryl consisting of 5-10 atoms containing 1,2,3 or 4 heteroatoms independently selected from O, S and N. In another embodiment, heteroaryl is a heteroaryl consisting of 5-6 atoms containing 1,2,3 or 4 heteroatoms independently selected from O, S and N. The heteroaryl group is optionally substituted with one or more substituents described herein.
Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 3534-triazolyl, thiazft 5248-thiazft, thiazft 5748-345732-thiazoyl, thiazofts-345732, thiazft-345732, thiazoyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyridyl, pyrazolo [1,5-a ] pyrimidyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.
The term "heteroarylalkyl" denotes an alkyl group substituted with one or more heteroaryl groups, wherein both the heteroaryl and alkyl groups have the meaning described herein, and such examples include, but are not limited to, pyridine-2-methyl, imidazole-2-methyl, furan-2-ethyl, indole-3-methyl, and the like.
The term "halogen" refers to F, cl, br or I.
As used herein, "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the descriptive pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences,1977, 66. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalatesSalts, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, pentanoates, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl radical) 4 A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
Description of the Compounds of the invention
The present invention discloses a novel class of pyrimidine amine compounds, which are useful as inhibitors of PI 3-kinase activity, in particular PI 3K-delta activity, for the prevention, treatment, and/or alleviation of diseases, disorders, and/or conditions associated with PI 3-kinase abnormalities, such as respiratory diseases, viral infections, non-viral respiratory infections, allergic diseases, autoimmune diseases, inflammatory diseases, cardiovascular diseases, hematological malignancies, neurodegenerative diseases, pancreatitis, multi-organ failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury or pain, and the like. Compared with the existing similar compounds, the compound has better pharmacological activity, and particularly shows excellent inhibitory activity and kinase selectivity on PI 3-kinase. Therefore, the compound has very good development prospect.
The compound disclosed by the invention can show stronger inhibitory activity on PI 3-kinase, especially on PI 3K-delta. In one aspect, the invention relates to a pyrimidinamine compound having a structure represented by formula (I):
or a stereoisomer, tautomer, nitroxide, solvate, or pharmaceutically acceptable salt thereof;
wherein the content of the first and second substances,
w is C 3-8 Cycloalkyl radical, C 2-9 Heterocyclic group, C 6-12 Aryl, or C 1-9 A heteroaryl group; wherein W is optionally substituted with 0,1, 2,3 or 4R 7 Substitution;
R a 、R b and R 1 Each independently H, D, F, -CN, -NO 2 、-NH 2 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl, or C 1-6 A cyanoalkyl group;
R 2 、R 4 、R 5 and R 6 Each independently is H, D, F, cl, br, I, -OH, -CN, -NO 2 、-NR e R f 、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 2-9 Heterocyclic group, C 3-8 Cycloalkyl, C 6-10 Aryl, or C 1-9 A heteroaryl group; wherein each C is 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 2-9 Heterocyclic group, C 3-8 Cycloalkyl radical, C 6-10 Aryl and C 1-9 Heteroaryl is independently optionally substituted with 0,1, 2,3 or 4 substituents independently selected from H, D, oxo (= O))、F、Cl、Br、I、-OH、-NH 2 、-CN、-NO 2 、C 1-6 Alkyl and C 1-6 A radical substitution of alkoxy;
R 3 is H, D, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, -NR 10a R 10 、-C(＝O)R 9 、-OC(＝O)R 9 、-C(＝O)OR 9a 、-S(＝O) 0-2 R 9 、-OS(＝O) 1-2 R 9 、-S(＝O) 1-2 OR 9a 、-N(R 10a )C(＝O)R 10 、-C(＝O)NR 10a R 10 、-OC(＝O)NR 10a R 10 、-N(R 10a )S(＝O) 1-2 R 10 、-S(＝O) 1-2 NR 10a R 10 、-N(R 10a )C(＝O)NR 10a R 10 、C 3-8 Cycloalkyl, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-9 Heterocyclic group, C 2-9 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 An alkyl group; wherein R is 3 Optionally substituted by 0,1, 2,3 or 4R 8 Substitution;
R 7 and R 8 Each occurrence is independently H, D, oxo (= O), F, cl, br, I, -OH, -CN, -NO 2 、-NH 2 、-C(＝O)R 9 、-OC(＝O)R 9 、-C(＝O)OR 9a 、-S(＝O) 0-2 R 9 、-OS(＝O) 1-2 R 9 、-S(＝O) 1-2 OR 9a 、-N(R 10a )C(＝O)R 10 、-C(＝O)NR 10a R 10 、-OC(＝O)NR 10a R 10 、-N(R 10a )S(＝O) 1-2 R 10 、-S(＝O) 1- 2 NR 10a R 10 、-N(R 10a )C(＝O)NR 10a R 10 、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-9 Heterocyclic group, C 2-9 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 An alkyl group; wherein each of the-C (= O) R 9 、-OC(＝O)R 9 、-C(＝O)OR 9a 、-S(＝O) 0-2 R 9 、-OS(＝O) 1-2 R 9 、-S(＝O) 1- 2 OR 9a 、-N(R 10a )C(＝O)R 10 、-C(＝O)NR 10a R 10 、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-9 Heterocyclic group, C 2-9 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl and C 1-9 Heteroaryl C 1-6 Alkyl is independently optionally substituted with 0,1, 2,3 or 4 substituents independently selected from H, D, oxo (= O), F, cl, br, -OH, -NH 2 、-CN、-NO 2 、C 1-6 Alkyl and C 1-6 A radical substitution of alkoxy; and
R e 、R f 、R 9 、R 9a 、R 10 and R 10a Independently at each occurrence H, D, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-9 Heterocyclic group, C 2-9 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radicalsC 1-6 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 An alkyl group; wherein each C is 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-9 Heterocyclic group, C 2-9 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl and C 1-9 Heteroaryl C 1-6 Alkyl is independently optionally substituted with 0,1, 2,3 or 4 groups independently selected from H, D, oxo (= O), F, cl, br, I, -OH, -NH 2 、-CN、-NO 2 、C 1-6 Alkyl and C 1-6 Alkoxy groups.
In some embodiments, W is C 3-6 Heterocyclyl, phenyl, or heteroaryl of 5 to 6 atoms; wherein W is optionally substituted with 0,1, 2,3 or 4R 7 And (4) substitution.
In some embodiments of the present invention, the substrate is, W is phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, thiadiazolyl, or,
Wherein Y is 1 Is O, S, or-NH-; and
wherein W is optionally substituted with 0,1, 2,3 or 4R 7 And (4) substitution.
In some embodiments, R a 、R b And R 1 Each independently of the other is H, D, F, cl, br, I, -OH, -CN, -NO 2 、-NH 2 Methyl, ethyl, methoxy, ethoxy, halomethyl, or haloethyl.
In some embodiments, R 2 is-NR e R f 、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 1-4 Haloalkyl, cyclopropyl, phenyl, or heteroaryl of 5 to 6 atoms; wherein each of said-NR e R f 、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 1-4 Haloalkyl, cyclopropyl, phenyl and heteroaryl of 5 to 6 atoms are independently optionally substituted with 0,1, 2,3 or 4 substituents independently selected from H, D, oxo (= O), F, cl, br, I, -OH, -NH 2 、-CN、-NO 2 、C 1-4 Alkyl and C 1-4 Alkoxy groups.
In some embodiments, R 2 Is H, D, F, cl, br, I, -OH, -CN, -NO 2 、-NH 2 Methyl, ethyl, isopropyl, methoxy, ethoxy, ethenyl, propenyl, ethynyl, propynyl, halomethyl, haloethyl, phenyl, or cyclopropyl.
In some embodiments, R 3 Is C 2-4 Alkenyl radical, C 2-4 Alkynyl, -NR 10a R 10 、-C(＝O)NR 10a R 10 、C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, phenyl, or heteroaryl of 5 to 6 atoms; wherein R is 3 Optionally substituted by 0,1, 2,3 or 4R 8 And (4) substitution.
In some embodiments, R 3 Is that
Ethenyl, ethynyl, -C (= O) NH-C 1-3 Alkyl, aryl, heteroaryl, and heteroaryl,
X 1 is O, S, -NH-, - (CH) 2 ) t1 -、-X 2 -(CH 2 ) t1 -, or- (CH) 2 ) t1 -X 2 -(CH 2 ) t2 -；
X 2 At each occurrence, is independently O, S, -NH-, or-CH 2 -；
X 3 Is O, S, or-NH-;
each t1 and t2 is independently 0,1, 2, or 3; and
n is 1,2 or 3;
wherein R is 3 Optionally substituted by 0,1, 2,3 or 4R 8 And (4) substitution.
In some embodiments, R 3 Is vinyl, ethynyl, -C (= O) NH-C 1-3 Alkyl, aryl, heteroaryl, and heteroaryl,
In some embodiments, R 4 、R 5 And R 6 Each independently is H, D, F, cl, br, I, -OH, -CN, -NO 2 、-NH 2 Methyl, ethyl, isopropyl, methoxy, ethoxy, ethenyl, propenyl, ethynyl, propynyl, halomethyl, haloethyl, phenyl, or cyclopropyl.
In some embodiments, R 7 And R 8 Each occurrence is independently H, D, oxo (= O), F, cl, br, I, -OH, -CN, -NO 2 、-NH 2 、-C(＝O)R 9 、-OC(＝O)R 9 、-C(＝O)OR 9a 、-S(＝O) 0-2 R 9 、-OS(＝O) 1-2 R 9 、-S(＝O) 1-2 OR 9a 、-N(R 10a )C(＝O)R 10 、-C(＝O)NR 10a R 10 、-OC(＝O)NR 10a R 10 、-N(R 10a )S(＝O) 1-2 R 10 、-S(＝O) 1-2 NR 10a R 10 、-N(R 10a )C(＝O)NR 10a R 10 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl radical, C 1-4 Aminoalkyl radical, C 1-4 Cyanoalkyl, C 1-4 Alkoxy radical, C 1-4 Alkylamino, cyclopropyl, C 3-6 Heterocyclyl, phenyl, or pyridyl; wherein each of the-C (= O) R 9 、-OC(＝O)R 9 、-C(＝O)OR 9a 、-S(＝O) 0-2 R 9 、-OS(＝O) 1-2 R 9 、-S(＝O) 1-2 OR 9a 、-N(R 10a )C(＝O)R 10 、-C(＝O)NR 10a R 10 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl radical, C 1-4 Aminoalkyl radical, C 1-4 Cyanoalkyl, C 1-4 Alkoxy radical, C 1-4 Alkylamino, cyclopropyl, C 3-6 Heterocyclyl, phenyl and pyridyl are independently optionally substituted with 0,1, 2,3 or 4 substituents independently selected from H, D, oxo (= O), F, cl, br, -OH, -NH 2 、-CN、-NO 2 、C 1-4 Alkyl and C 1-4 Alkoxy groups.
In some embodiments, R e 、R f 、R 9 、R 9a 、R 10 And R 10a Independently at each occurrence H, D, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyl radical C 1-6 Alkyl radical, C 3-6 Heterocyclic group, C 3-6 Heterocyclyl radical C 1-4 Alkyl radical, C 6-10 Aryl radical, C 6-10 Aryl radical C 1-4 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-4 An alkyl group; wherein each C is 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyl radical C 1-6 Alkyl radical, C 3-6 Heterocyclic group, C 3-6 Heterocyclyl radical C 1-4 Alkyl radical, C 6-10 Aryl radical, C 6-10 Aryl radical C 1-4 Alkyl radical, C 1-9 Heteroaryl and C 1-9 Heteroaryl C 1-4 Alkyl is independently optionally substituted with 0,1, 2,3 or 4 substituents independently selected from H, D, oxo (= O)F、Cl、Br、I、-OH、-NH 2 、-CN、-NO 2 、C 1-4 Alkyl and C 1-4 Alkoxy groups.
In some embodiments, R 7 And R 8 Each occurrence is independently H, D, oxo (= O), F, cl, br, I, -OH, -CN, -NO 2 、-NH 2 、-CH 3 、-CH 2 CH 3 、-CH(CH 3 )CH 3 、-CH 2 CH(OH)CH 3 、-CH 2 CH 2 OH、-CF 3 、-CH 2 CF 3 A cyclopropyl group,
In some embodiments, wherein the compound is a compound having one of the following structures:
or a stereoisomer, tautomer, nitroxide, solvate, or pharmaceutically acceptable salt thereof.
Unless otherwise indicated, stereoisomers, tautomers, solvates, metabolites or pharmaceutically acceptable salts of the compounds of formula (I) are included within the scope of the present invention.
The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are integral to the invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well defined and defined.
The compounds of formula (I) may exist in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salts need not be pharmaceutically acceptable salts and may be intermediates useful in the preparation and/or purification of compounds of formula (I) and/or in the isolation of enantiomers of compounds of formula (I).
In another aspect, the invention relates to intermediates for the preparation of compounds of formula (I).
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, diluent or carrier, or a combination thereof. In another embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.
In some embodiments, the pharmaceutical compositions of the present invention further comprise an additional therapeutic agent.
In another aspect, the invention relates to a use of a compound described herein or a pharmaceutical composition described herein for the manufacture of a medicament for preventing, treating, and/or alleviating a disease, disorder, and/or condition associated with an abnormality of PI 3-kinase, or inhibiting PI 3-kinase activity.
In some embodiments, the PI 3-kinase abnormality associated disease, disorder, and/or condition is selected from respiratory disease, viral infection, non-viral respiratory infection, allergic disease, autoimmune disease, inflammatory disease, cardiovascular disease, hematologic malignancy, neurodegenerative disease, pancreatitis, multi-organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury, or pain.
In some embodiments, the PI 3-kinase abnormality associated disease, disorder, and/or condition is selected from asthma, chronic Obstructive Pulmonary Disease (COPD), viral respiratory infection, viral respiratory disease exacerbation, aspergillosis, leishmaniasis, allergic rhinitis, allergic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematological malignancies, neurodegenerative disease, pancreatitis, multiorgan failure, renal disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury, pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, posthepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia or central pain.
In some embodiments, the cancer is selected from acute myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorder, chronic myelogenous leukemia, T-cell acute lymphocytic leukemia, B-cell acute lymphocytic leukemia, non-hodgkin's lymphoma, B-cell lymphoma, solid tumor, or breast cancer.
In some embodiments, wherein the PI 3-kinase is PI3K- δ.
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The present invention provides a pharmaceutical composition comprising a compound disclosed herein, or a compound listed in the examples, or a stereoisomer, tautomer, nitric oxide, solvate, metabolite, or pharmaceutically acceptable salt thereof; and pharmaceutically acceptable adjuvants, diluents, carriers, vehicles or combinations thereof. The amount of compound in the pharmaceutical compositions disclosed herein is an amount effective to detectably inhibit a protein kinase in a biological sample or patient.
It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the invention or a metabolite or residue thereof.
Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in, for example, remington, the Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, lippincott Williams and Wilkins, philadelphia, and Encyclopedia of Pharmaceutical technology, eds.J.Swarbrick and J.C.Boylan,1988-1999, marcel Dekker, new York, the contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the disclosed compounds, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.
The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.
Use of the Compounds and compositions of the invention
The compounds of the present invention are inhibitors of kinase activity, particularly PI 3-kinase activity. Compounds that are inhibitors of PI 3-kinase may be useful in the treatment of disorders in which the underlying pathology is (at least in part) due to inappropriate PI 3-kinase activity, such as asthma, chronic Obstructive Pulmonary Disease (COPD), viral infections, non-viral respiratory infections, allergic diseases, autoimmune diseases, inflammatory diseases, cardiovascular diseases, hematological malignancies, neurodegenerative diseases, pancreatitis, multi-organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury or pain, and the like. By "inappropriate PI 3-kinase activity" is meant any PI 3-kinase activity that deviates from the normal PI 3-kinase activity expected in a particular patient. Inappropriate PI 3-kinases may take the form of, for example, an abnormal increase in activity, or an aberration in PI 3-kinase or dysregulation. These inappropriate activities may result, for example, from overexpression or mutation of protein kinases that result in inappropriate or uncontrolled activation. Thus, in another aspect, the invention relates to a method of treating said disease or disorder.
Such diseases or conditions include, but are not limited to, respiratory diseases including asthma, chronic obstructive pulmonary disease, and Idiopathic Pulmonary Fibrosis (IPF); viral infections, including viral respiratory infections and viral exacerbations of respiratory diseases, such as asthma and COPD; non-viral respiratory infections including aspergillosis and leishmaniasis; allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease; cardiovascular diseases including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; pancreatitis; multiple organ failure; kidney disease; platelet aggregation; cancer; sperm motility; transplant rejection; graft rejection; lung injury; and pain, including pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, posthepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia, and central pain. In one embodiment, such disorders include respiratory diseases, including asthma and Chronic Obstructive Pulmonary Disease (COPD); allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease; cardiovascular diseases including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; pancreatitis; multiple organ failure; kidney disease; platelet aggregation; cancer; sperm motility; transplant rejection; graft rejection; lung injury; and pain, including pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, posthepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia and central pain.
In such diseases or conditions, the cancer is selected from acute myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorders, chronic myelogenous leukemia, T-cell acute lymphocytic leukemia, B-cell acute lymphocytic leukemia, non-hodgkin's lymphoma, B-cell lymphoma, solid tumors, or breast cancer.
The treatment methods of the present invention comprise administering to a patient in need thereof a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Various embodiments of the present invention include methods of treating any one of the disorders or diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Combination therapy
The compounds of the present invention may be administered as the sole active agent or may be administered in combination with other therapeutic agents, including other compounds that have the same or similar therapeutic activity and are identified as safe and effective for such combination administration.
In one aspect, the invention provides a method of treating, preventing or ameliorating a disease or disorder, comprising administering a safe and effective amount of a combination comprising a compound disclosed herein and one or more therapeutically active agents. In some embodiments, the combination comprises one or two additional therapeutic agents.
Examples of other therapeutic agents include, but are not limited to: anti-cancer agents, including chemotherapeutic agents and antiproliferative agents; an anti-inflammatory agent; and an immunomodulator or immunosuppressant.
In another aspect, the invention provides products comprising a compound of the invention and at least one other therapeutic agent, formulated for simultaneous, separate or sequential administration in therapy. In some embodiments, the treatment is for a disease or condition mediated by one or more protein kinases, such as PI3 k-kinase activity. The combined preparation provides products including compositions comprising the disclosed compounds and other therapeutic agents in the same pharmaceutical composition, or in different forms, e.g., kits.
In another aspect, the invention provides a pharmaceutical composition comprising a compound disclosed herein and one or more additional therapeutic agents. In some embodiments, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient as described above.
In another aspect, the invention provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition comprises a compound disclosed herein. In some embodiments, the kit comprises means for separately holding the compositions, such as a container, a separate bottle, or a separate foil box. An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules and the like.
The compounds disclosed herein may be administered as a single active ingredient or as, for example, an adjuvant, co-administered with other therapeutic agents.
In some embodiments, the additional therapeutic agent includes, for example, an immunosuppressive, immunomodulatory or other anti-inflammatory agent, a drug for treating or preventing allo-or xenotransplant acute or chronic rejection, or inflammation, or an autoimmune disease, or a chemotherapeutic agent, such as a malignant cell antiproliferative agent.
The compounds of formula (I) of the present invention are co-administered with other immunosuppressive/immunomodulatory, anti-inflammatory, chemotherapeutic or anti-infective agents, wherein the dosage of the immunosuppressive/immunomodulatory, anti-inflammatory, chemotherapeutic or anti-infective agent co-administered depends on the type of co-administration, whether it is a steroid or a calcineurin inhibitor, and the particular drug being used for treatment and the condition being treated, etc.
Examples of anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs). Examples of NSAIDs include cromolyn sodium, nedocromil sodium (sodium), phosphodiesterase (PDE) inhibitors (such as theophylline, PDE4 inhibitors, or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, leukotriene synthesis inhibitors (such as montelukast), iNOS inhibitors, trypsin and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (such as adenosine 2 alpha receptor agonists), cytokine antagonists (such as chemokine receptor antagonists, including CCR3 antagonists), cytokine synthesis inhibitors, or 5-lipoxygenase inhibitors.
The compounds of formula (I) may also be advantageously employed in combination with other compounds, or in combination with other therapeutic agents, especially antiproliferative agents. Such antiproliferative agents include, but are not limited to, aromatase inhibitors; an antiestrogen; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active agent; an alkylating agent; (ii) histone deacetylase inhibitors; compounds that induce a cellular differentiation process; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; an antineoplastic antimetabolite; a platinum compound; compounds that target/reduce protein or lipid kinase activity and other anti-angiogenic compounds; a compound that targets, reduces or inhibits protein or lipid phosphatase activity; gonadorelin agonists; an antiandrogen; methionine aminopeptidase inhibitors; a bisphosphonate; a biological response modifier; an anti-proliferative antibody; heparanase inhibitors; ras oncogenic subtype inhibitors; a telomerase inhibitor; a proteasome inhibitor; agents for treating hematological tumors; compounds that target, decrease or inhibit Flt-3 activity; an Hsp90 inhibitor; temozolomide and calcium folinate.
"combination" means a fixed combination or a kit of parts for the administration of a combination in the form of a single dosage unit, in which a compound disclosed in the invention and a combination partner may be administered separately at the same time or may be administered separately at certain time intervals, in particular such that the combination partners exhibit a cooperative, e.g. synergistic, effect. The terms "co-administration" or the like as used herein are intended to encompass administration of the selected combination partner to a single individual in need thereof (e.g., a patient), and are intended to encompass treatment regimens in which the substances are not necessarily administered by the same route of administration or simultaneously.
Method of treatment
In some embodiments, the presently disclosed methods of treatment comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Various embodiments disclosed herein include methods of treating a disease or condition described herein by administering to a patient in need thereof a safe and effective amount of a disclosed compound or a pharmaceutical composition comprising a disclosed compound.
In some embodiments, a disclosed compound or pharmaceutical composition comprising a disclosed compound may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds depend on the pharmacokinetic properties of the compound, such as dilution, distribution and half-life, which can be determined by the skilled person. In addition, suitable dosing regimens for the compounds or pharmaceutical compositions comprising the disclosed compounds, including the duration of the regimen, will depend upon the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and experience of the skilled artisan. It will also be appreciated by those skilled in the art that adjustment of an appropriate dosage regimen may be required for the individual patient's response to the dosage regimen, or as the individual patient needs to change over time.
The pharmaceutical composition or combination/association of the invention may be a unit dose of about 1-1000mg of the active ingredient, or about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg, or about 1-50mg of the active ingredient for about 50-70kg of an individual. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof will depend on the species, weight, age of the individual and the disease, disorder or condition of the individual or the severity of the condition to be treated. A physician, clinician or veterinarian of ordinary skill in the art can readily determine the effective amount of each active ingredient to prevent, treat or inhibit the progression of the disease or condition. The above-cited dose profiles have been demonstrated in vitro and in vivo assays using beneficial mammals, e.g., mice, rats, dogs, monkeys, or isolated organs, tissues and specimens thereof. The compounds of the invention can be used in vitro in the form of solutions, for example aqueous solutions, and in vivo in the form of suspensions or aqueous solutions, enterally, parenterally and, where appropriate, intravenously. The therapeutically effective amount in vivo ranges from about 0.01 to about 500mg/kg, or from about 1 to about 100mg/kg, depending on the route of administration.
The presently disclosed compounds may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or in the same pharmaceutical composition.
General synthetic schemes
To describe the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples, but is provided only to practice the invention.
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, alfa Chemical Company, shanghai Yangshao reagent, inc., SAIN Chemical technology (Shanghai), shanghai Bierde pharmaceutical technology, inc., shanghai Hao biomedical technology, inc. unless otherwise indicated, reagents used in the present invention can be used without further purification. The solvent is commercially available from commercial suppliers such as VISCO technologies, inc., of Beijing Hai.
Anhydrous THF, dioxane, DCM, toluene and DMF were all purchased from commercial suppliers such as An Naiji (Energy chemical company) and Aldrich chemical company. EtOAc, PE, CH 3 CN, NMP and DMSO were treated with anhydrous Na before use 2 SO 4 And (6) processing.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
Chromatography the column is a silica gel column was used. Silica gel (300-400 mesh) was purchased from Qingdao oceanic plants.
1 H NMR spectrum and 13 C/2D data were collected at 400MHz of Bruker Avance III. 1 H NMR spectrum with CDC1 3 、DMSO-d 6 、CD 3 OD or acetone-d 6 TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singlets), d (doublets), t (triplets), m (multiplets), br (broad singlets), dd (doublets of doublets), dt (doublets of triplets). Coupling constants are expressed in hertz (Hz).
The LC/MS was performed on an Agilent 1260 (binary pump/DAD detector) coupled to an Agilent 6120/6125 mass spectrometer.
The method comprises the following steps:
column: HALO C18.7 μm,4.6mm × 30mm, mobile phase: meCN (0.05% HCOOH) -Water (0.05% HCOOH); gradient: eluting from 5% to 95% MeCN for 0.8min, and keeping for 0.8min, wherein the total running time is 2.0min; flow rate: 1.8mL/min; column temperature: 45 ℃;
the method 2 comprises the following steps:
column: HALO C18.7 μm,4.6mm × 50mm, mobile phase: meCN (0.025% trifluoroacetic acid) -water (0.025% trifluoroacetic acid); gradient: eluting from 5% to 95% MeCN for 1.0min, maintaining for 1.0min, and keeping total running time for 2.5min; flow rate: 1.8mL/min; column temperature: at 45 deg.c.
Purity testing by RP-HPLC:
compound purity testing was performed on RP-HPLC (Shimadzu 2010/2030)
The method comprises the following steps:
column: gemini 4.6 multiplied by 150mm 5um; mobile phase: h 2 O (0.05% trifluoroacetic acid) -MeCN (0.05% trifluoroacetic acid). Gradient:
from 10% to 100% MeCN, elute 8 minutes, hold 2 minutes. Flow rate: 1.2mL/min, column temperature: 35 ℃/40 ℃. The method 2 comprises the following steps:
column: XBRIDGE 2.1X 50mm,3.5um; mobile phase: h 2 O (0.05% trifluoroacetic acid) -MeCN (0.05% trifluoroacetic acid). Ladder with adjustable height
Degree: from 10% to 100% MeCN, elute 7 minutes, hold 1 minute. Flow rate: 0.8mL/min, column temperature: 35 ℃/40 ℃.
Compound purification by SFC:
SFC purification was performed on a THar P80 equipped with a UV detector.
The method comprises the following steps: column CHIRALPAK AD-H250mm, 20mm,5 μm, modifier: 30% EtOH (0.2% NH) 4 OH)。
Compound purification by RP-HPLC:
RP-HPLC purification was performed on a Gilson purification system (322 or 306 pumps and GX-281 fraction collector), shimadzu LC20Ap and Waters MS-triggered purification system;
the method comprises the following steps:
column Gemini C18 21x150mm,5 μm Xbridge C18 19x150mm,5 μm, spolar C18 x150mm and Ultimate AQ-C18 30x250mm,10 μm
Mobile phase:
aqueous solution of mecn (0.1% hcooh), flow rate: 20ml/min,50ml/min, column 30x250mm,10 μm; wavelength: 210-400nm. Samples were injected into DMSO (+ optionally formic acid and water) and eluted for 10 minutes from a linear gradient of 10% to 95% mecn.
Aqueous solution of mecn (0.1% trifluoroacetic acid), flow rate: 20ml/min,50ml/min, column 30x250mm,10 μm; wavelength: 210-400nm. Samples were injected into DMSO (+ optionally formic acid and water) and eluted for 10 minutes from a linear gradient of 10% to 95% mecn.
Aqueous solution of MeCN (0.1% NH) 3 -H 2 O/10mM NH 4 AC), flow rate: 20ml/min,50ml/min, column 30x250mm,10 μm; wavelength: 210-400nm. Samples were injected into DMSO (+ optionally formic acid and water) and eluted for 10 minutes from a linear gradient of 10% to 95% mecn.
Typical synthetic procedures for preparing the disclosed compounds are shown in scheme 1 below. Unless otherwise indicated, R 1 、R 2 、R 3 、R 4 、R 5 、R a 、R b And W both have the definitions as described herein.
Synthesis scheme 1:
the compounds of formula I of the present invention can be synthesized as shown in scheme 1. Compounds (i) can be acylated with acylating agents (e.g. R) a R b -COCl) to form an ester, which can be rearranged under Lewis acid conditions to give ketone (ii). Using NX 1 S(NX 1 S = N-chlorobutanediamide, N-bromobutanediamide or N-iodobutanediamide) to give compound (iii) wherein X 1 = Cl, br or I. Phenol can be used with standard conditions (e.g., tf) 2 O) to the triflate (iv). (iv) The triflate group of (A) can be reacted with R under standard Suzuki (Suzuki) conditions or standard Stille (Stille) conditions or standard root bank (Negishi) conditions 2 Coupling of M to give a derivative of (v), wherein M is boronic acid, boronic ester or suitably substituted metal (e.g. R) 2 -Sn(Bu) 4 Or Zn-R 2 ). Or, R 2 -M may be an alkyl ether (wherein M is H and is attached to a hydroxyl group) whose nucleophilic substitution with compound (iii) is carried out by heating under basic conditions to give the derivative of formula (v). Compound (v) can be heated under acidic conditions using ethylene glycol to give compound (vi). (vi) X of (2) 1 The groups can be in standard Suzuki (Suzuki) conditions or standardsWith R under quasi-still (Stille) conditions or standard root-bank (Negishi) conditions 3 -M coupling, wherein M is a boronic acid, boronic ester or appropriately substituted metal (e.g. R) 3 -B(OH) 2 、R 3 -Sn(Bu) 4 Or Zn-R 3 ) To obtain the derivative of (vii). Compound (vii) is deprotected under acidic conditions to give (viii), and heated with hydroxylamine hydrochloride in pyridine to give compound (ix). Compound (ix) is reacted with ammonia with a suitable reducing agent (e.g., raney nickel, etc.) to give a derivative of (x). (xi) Heating with compound (x) under basic conditions to give compound (xii) of formula I of the present invention.
Examples
Example 1- (3- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
Step 1) 1- (5-chloro-4-fluoro-2-hydroxyphenyl) ethan-1-one
To 4-chloro-3-fluorophenol (3g, 0.02mol) and AlCl 3 Acetyl chloride (1.93g, 0.024mol) was added (5.47g, 0.04mol) to a mixture of DCM (10 mL) and the mixture was stirred at 25 ℃ for 2h. The DCM was then distilled and the residue was heated to 140 ℃ for 2h. After cooling to room temperature, the mixture was quenched with 10% HCl (20 mL) and the solid was filtered. The filter cake was washed with water (20 mL) and dried in vacuo to give 1- (5-chloro-4-fluoro-2-hydroxyphenyl) ethan-1-one (4 g,93% yield) as a brown solid. MS (ESI) 187.0[ M-H ]] - 。 1 H NMR(400MHz,DMSO)δ12.17(s,1H),8.07(d,J＝8.4Hz,1H),7.07(d,J＝10.8Hz,1H),2.63(s,3H)。
Step 2) 1- (5-chloro-4-fluoro-2-hydroxy-3-iodophenyl) ethan-1-one
To a solution of 1- (5-chloro-4-fluoro-2-hydroxyphenyl) ethanone (3 g,15.9 mmol) in HOAc (30 mL) was added NIS (4.3 g, 19mmol) and the mixture was heated to 80 ℃ for 16h. The mixture is mixed with Na 2 SO 3 The aqueous solution (20 mL) was quenched and the mixture was concentrated in vacuo. The residue was diluted with EtOAc (60 mL) and thenBrine (30 mL. Times.3). The separated organic layer was washed with Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by silica gel chromatography (EA/PE = 1/5) to give 1- (5-chloro-4-fluoro-2-hydroxy-3-iodophenyl) ethan-1-one (4 g,76% yield) as a yellow solid. MS (ESI) 314.9[ 2 ] M + H] + 。 1 H NMR(400MHz,CDCl 3 )δ13.44(d,J＝2.0Hz,1H),7.83(d,J＝8.0Hz,1H),2.66(s,3H)。
Step 3) 1- (5-chloro-2-ethoxy-4-fluoro-3-iodophenyl) ethan-1-one
To 1- (5-chloro-4-fluoro-2-hydroxy-3-iodophenyl) ethanone (1.1g, 3.5mmol) and K 2 CO 3 To a solution of (0.97g, 7 mmol) in DMF (5 mL) was added iodoethane (0.82g, 5.2mmol) and the mixture was heated at 60 ℃ for 2h. After cooling to room temperature, the mixture was diluted with EtOAc (40 mL) and washed with brine (30 mL. Times.3). The separated organic layer was washed with Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by silica gel chromatography (EA/PE = 1/5) to give 1- (5-chloro-2-ethoxy-4-fluoro-3-iodophenyl) ethan-1-one (1.2g, 91% yield) as a yellow oil. MS (ESI) 342.7[ deg. ] M + H] + 。 1 H NMR(400MHz,CDCl 3 )δ7.71(d,J＝8.4Hz,1H),3.97(q,J＝6.8Hz,2H),2.63(s,3H),1.50(t,J＝6.8Hz,4H)。
Step 4) 2- (5-chloro-2-ethoxy-4-fluoro-3-iodophenyl) -2-methyl-1,3-dioxolane
To a solution of 1- (5-chloro-2-ethoxy-4-fluoro-3-iodophenyl) ethanone (1.2g, 3.5 mmol) and ethylene glycol (0.43g, 7 mmol) in toluene (30 mL) was added PTSA (60mg, 0.3 mmol) and the mixture was heated at reflux with a Dean-Stark trap for 16h. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL) and then NaHCO 3 (30 mL) aqueous solution. The separated organic layer was washed with Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by silica gel chromatography (EA/PE = 1/5) to give 2- (5-chloro-2-ethoxy-4-fluoro-3-iodophenyl) -2-methyl-1,3-dioxolane (1g, 71% yield) as a colorless oil. MS (ESI) 386.8[ m ] +H] + 。 1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝8.8Hz,1H),4.13-4.05(m,3H),3.85-3.82(m,2H),1.74(s,3H),1.50(t,J＝6.8Hz,3H)。
Step 5) Ethyl 3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) acrylate
2- (5-chloro-2-ethoxy-4-fluoro-3-iodophenyl) -2-methyl-1,3-dioxolane (800mg, 2.07mmol), prop-2-enoic acid ethyl ester (414mg, 4.14mmol), palladium diacetate (46.5mg, 0.2mmol), tri-o-tolylphosphine (63mg, 0.2mmol) and Et 3 A solution of N (419mg, 4.14mmol) in DMA (20 mL) was heated at 90 ℃ for 16 hours. After cooling to room temperature, the mixture was diluted with EtOAc (70 mL) and washed with brine (30 mL. Times.3). The separated organic layer was washed with Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by silica gel chromatography (EA/PE = 1/5) to give ethyl (E) -3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) acrylate (650mg, 83.2% yield) as a colorless oil. MS (ESI): 359.1[ m ] +H] + 。
Step 6) Ethyl 3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) -4-nitrobutanoate
A solution of ethyl (E) -3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) acrylate (1g, 2.8mmol)) in nitromethane (0.85g, 14mmol) was added DBU (0.47g, 3mmol) and the mixture was stirred at 60 ℃ for 16h. The mixture was diluted with EtOAc (60 mL) and then washed with brine (40 mL. Times.2). The separated organic layer was washed with Na 2 SO 4 Dried, concentrated in vacuo, and the residue purified by silica gel chromatography (EA/PE = 1/5) to give ethyl 3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) -4-nitrobutanoate (500mg, 39.3% yield) as a colorless oil. MS (ESI) 420.1[ 2 ] M + H] + 。 1 H NMR(400MHz,CDCl 3 )δ7.54(d,J＝8.8Hz,1H),4.86-4.80(m,1H),4.72-4.66(m,1H),4.53-4.43(m,1H),4.12(q,J＝7.1Hz,2H),4.08-4.00(m,3H),3.87-3.80(m,2H),2.90-2.83(m,1H),2.78-2.72(m,1H),1.72(s,3H),1.49(t,J＝6.8Hz,3H),1.23(t,J＝7.2Hz,3H)。
Step 7) 4- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) pyrrolidin-2-one
3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl)A solution of ethyl-4-nitrobutanoate (500mg, 0.43mmol) and Raney nickel (70mg, 1.19mmol) in EtOH (20 mL) was treated with H 2 Balloon hydrogenation, and the mixture was stirred at 25 ℃ for 2h. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was dissolved in toluene (30 mL) and the mixture was heated at 110 ℃ for 16h. After cooling to room temperature, the mixture was concentrated in vacuo, 4- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) pyrrolidin-2-one (400mg, 78% yield) was obtained as a white solid. MS (ESI) 344.1[ m ] +H] + 。
Step 8) 4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
To a solution of 4- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) pyrrolidin-2-one (400mg, 1.16mmol) in MeOH (20 mL) was added 6N HCl (4 mL) and the mixture was stirred at 25 deg.C for 16h. The mixture was concentrated in vacuo and the residue was taken up in NaHCO 3 Aqueous solution (20 mL). The mixture was extracted with EtOAc (30mL. Times.2) and the combined organic layers were washed with brine (30 mL) and Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by silica gel chromatography (PE/EA = 1/2) to give 4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (200mg, 48.5% yield) as a white solid. MS (ESI) 300.1[ 2 ] M + H] + 。 1 H NMR(400MHz,CDCl 3 )δ7.60(d,J＝8.4Hz,1H),4.26-4.17(m,1H),3.86(q,J＝7.2Hz,2H),3.73-3.68(m,2H),3.63-3.58(m,1H),2.75-2.65(m,2H),2.61(s,3H),1.43(t,J＝7.2Hz,3H)。
Step 9) (E) -4- (3-chloro-6-ethoxy-2-fluoro-5- (1- (hydroxyimino) ethyl) phenyl) pyrrolidin-2-one
To a solution of 4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (50mg, 0.17mmol) and pyridine (26mg, 0.33mmol) in EtOH (20 mL) was added NH 2 OH.HCl (13mg, 0.18mmol) and the mixture was heated at 70 ℃ for 16h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL. Times.2). The separated organic layer was washed with Na 2 SO 4 Dried and concentrated in vacuo to give (E) -4- (3-chloro-6-ethoxy-2-fluoro-5- (1- (hydroxyimino) ethyl) phenyl) pyrrolidin-2-one (50mg, 85% yield)As a yellow solid. MS (ESI) 315.0[ m ] +H] + 。
Step 10) 4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
(E) -4- (3-chloro-6-ethoxy-2-fluoro-5- (1- (hydroxyimino) ethyl) phenyl) pyrrolidin-2-one (35mg, 0.11mmol), raney's nickel (7 mg, 0.11mmol) and thiophene (9.4mg, 0.11mmol) in MeOH (10 mL) and NH 3 .H 2 The O (1 mL) mixture was hydrogenated at 25 ℃ for 16h. The mixture was then filtered and the filtrate was concentrated in vacuo to give 4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (30mg, 71.8% yield) as a white solid. MS (ESI) 283.9[ M-NH ] 3 +H] + 。
Step 11) 4- (3- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
A solution of 4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (30mg, 0.1mmol), 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (21mg, 0.1mmol) and DIEA (26mg, 0.2mmol) in 2-pentanol (10 mL) was heated at 90 ℃ for 16 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (60 mL) and washed with brine (40 mL. Times.2). The separated organic layer was passed over Na 2 SO 4 Drying and vacuum concentrating. The residue was subjected to preparative HPLC (ACN-H) 2 O0.1 FA, gradient 40% to 60%) to give 4- (3- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (20mg, 40% yield) as a white solid. MS (ESI) 476.1[ m ] +H] + 。 1 H NMR(400MHz,DMSO)δ8.53(d,J＝7.2Hz,1H),8.00(d,J＝2.4Hz,1H),7.83(s,1H),7.71-7.55(m,2H),7.49(d,J＝8.4,1H),5.62-5.56(m,1H),4.15-4.09(m,1H),4.06-4.00(m,1H),3.91-3.83(m,1H),3.64-3.55(m,1H),3.30-3.22(m,1H),2.61-2.55(m,1H),2.45(s,3H),2.40-2.34(m,1H),1.47(d,J＝6.8Hz,3H),1.41(t,J＝6.8,3H)。
Example 2- (3- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
Step 1) 1- (5-chloro-4-fluoro-2-hydroxyphenyl) ethan-1-one
To 4-chloro-3-fluorophenol (3g, 0.02mol) and AlCl 3 Acetyl chloride (1.93g, 0.024mol) was added (5.47g, 0.04mol) to a mixture of DCM (10 mL) and the resulting mixture was stirred at 25 ℃ for 2h. DCM was then distilled and the residue was heated at 140 ℃ for 2h. After cooling to room temperature, the mixture was quenched with 10% HCl (20 mL) and the solid was filtered. The filter cake was washed with water (20 mL) and dried in vacuo to give 1- (5-chloro-4-fluoro-2-hydroxyphenyl) ethan-1-one (4 g,93% yield) as a brown solid. MS (ESI) 187.0[ M-H ], [] - 。 1 H NMR(400MHz,DMSO)δ12.17(s,1H),8.07(d,J＝8.4Hz,1H),7.07(d,J＝10.8Hz,1H),2.63(s,3H)。
Step 2) 1- (5-chloro-4-fluoro-2-hydroxy-3-iodophenyl) ethan-1-one
To a solution of 1- (5-chloro-4-fluoro-2-hydroxyphenyl) ethanone (3 g,15.9 mmol) in HOAc (30 mL) was added NIS (4.3 g, 19mmol) and the mixture was heated to 80 ℃ for 16h. The mixture is mixed with Na 2 SO 3 The aqueous solution (20 mL) was quenched and the mixture was concentrated in vacuo. The residue was diluted with EtOAc (60 mL) and washed with brine (30 mL. Times.3). The separated organic layer was passed over Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by silica gel chromatography (EA/PE = 1/5) to give 1- (5-chloro-4-fluoro-2-hydroxy-3-iodophenyl) ethan-1-one (4 g,76% yield) as a yellow solid. MS (ESI) 314.9[ 2 ] M + H] + 。 1 H NMR(400MHz,CDCl 3 )δ13.44(d,J＝2.0Hz,1H),7.83(d,J＝8.0Hz,1H),2.66(s,3H)。
Step 3) 1- (5-chloro-2-ethoxy-4-fluoro-3-iodophenyl) ethan-1-one
To 1- (5-chloro-4-fluoro-2-hydroxy-3-iodophenyl) ethanone (1.1g, 3.5mmol) and K 2 CO 3 To a solution of (0.97g, 7 mmol) in DMF (5 mL) was added iodoethane (0.82g, 5.2mmol) and the mixture was heated at 60 ℃ for 2h. After cooling to room temperature, the mixture was diluted with EtOAc (40 mL) and washed with brine (30 mL. Times.3). The separated organic layer was washed with Na 2 SO 4 DryingAnd (4) concentrating in vacuum. The residue was purified by silica gel chromatography (EA/PE = 1/5) to give 1- (5-chloro-2-ethoxy-4-fluoro-3-iodophenyl) ethan-1-one (1.2g, 91% yield) as a yellow oil. MS (ESI): 342.7
[M+H] + 。 1 H NMR(400MHz,CDCl 3 )δ7.71(d,J＝8.4Hz,1H),3.97(q,J＝6.8Hz,2H),2.63(s,3H),1.50(t,J＝6.8Hz,4H)。
Step 4) 2- (5-chloro-2-ethoxy-4-fluoro-3-iodophenyl) -2-methyl-1,3-dioxolane
To a solution of 1- (5-chloro-2-ethoxy-4-fluoro-3-iodophenyl) ethanone (1.2g, 3.5 mmol) and ethylene glycol (0.43g, 7 mmol) in toluene (30 mL) was added PTSA (60mg, 0.3 mmol) and the mixture was heated at reflux with a Dean-Stark trap for 16h. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL) and NaHCO 3 (30 mL) aqueous solution. The separated organic layer was passed over Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by silica gel chromatography (EA/PE = 1/5) to give 2- (5-chloro-2-ethoxy-4-fluoro-3-iodophenyl) -2-methyl-1,3-dioxolane (1g, 71% yield) as a colorless oil. MS (ESI) 386.8[ 2 ], [ M ] +H] + 。 1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝8.8Hz,1H),4.13-4.05(m,3H),3.85-3.82(m,2H),1.74(s,3H),1.50(t,J＝6.8Hz,3H)。
Step 5) Ethyl 3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) acrylate
2- (5-chloro-2-ethoxy-4-fluoro-3-iodophenyl) -2-methyl-1,3-dioxolane (800mg, 2.07mmol), prop-2-enoic acid ethyl ester (414mg, 4.14mmol), palladium diacetate (46.5mg, 0.2mmol), tri-o-tolylphosphine (63mg, 0.2mmol) and Et 3 A solution of N (419mg, 4.14mmol) in DMA (20 mL) was heated at 90 ℃ for 16 hours. After cooling to room temperature, the mixture was diluted with EtOAc (70 mL) and washed with brine (30 mL. Times.3). The separated organic layer was washed with Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by silica gel chromatography (EA/PE = 1/5) to give ethyl (E) -3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) acrylate (650mg, 83.2% yield) as a colorless oil. MS (ESI): 359.1[ m ] +H] + 。
Step 6) Ethyl 3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) -4-nitrobutanoate
To a solution of ethyl (E) -3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) acrylate (1g, 2.8mmol) in nitromethane (0.85g, 14mmol) was added DBU (0.47g, 3mmol) and the mixture was stirred at 60 ℃ for 16h. The mixture was diluted with EtOAc (60 mL) and then washed with brine (40 mL. Times.2). The separated organic layer was passed over Na 2 SO 4 Dried, concentrated in vacuo, and the residue purified by silica gel chromatography (EA/PE = 1/5) to give ethyl 3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) -4-nitrobutanoate (500mg, 39.3% yield) as a colorless oil. MS (ESI) 420.1[ 2 ] M + H] + 。 1 H NMR(400MHz,CDCl 3 )δ7.54(d,J＝8.8Hz,1H),4.86-4.80(m,1H),4.72-4.66(m,1H),4.53-4.43(m,1H),4.12(q,J＝7.1Hz,2H),4.08-4.00(m,3H),3.87-3.80(m,2H),2.90-2.83(m,1H),2.78-2.72(m,1H),1.72(s,3H),1.49(t,J＝6.8Hz,3H),1.23(t,J＝7.2Hz,3H)。
Step 7) 4- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) pyrrolidin-2-one
A solution of ethyl 3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) -4-nitrobutanoate (500mg, 0.43mmol) and Raney's nickel (70mg, 1.19mmol) in EtOH (20 mL) was treated with H 2 The spheres were hydrogenated and the mixture was stirred at 25 ℃ for 2h. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was dissolved in toluene (30 mL) and the mixture was heated at 110 ℃ for 16h. After cooling to room temperature, the mixture was concentrated in vacuo to give ethyl 3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) -4-nitrobutanoate (400mg, 78% yield) as a white solid. MS (ESI) 344.1[ m ] +H] + 。
Step 8) 4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
To a solution of ethyl 3- (3-chloro-6-ethoxy-2-fluoro-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) -4-nitrobutanoate (400mg, 1.16mmol) in MeOH (20 mL) was added 6N HCl (4 mL) and the mixture was mixedThe mixture was stirred at 25 ℃ for 16 hours. The mixture was concentrated in vacuo and the residue was taken up in NaHCO 3 (20 mL) diluted with an aqueous solution. The mixture was extracted with EtOAc (30mL. Times.2) and the combined organic layers were washed with brine (30 mL) and Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by silica gel chromatography (PE/EA = 1/2) to give 4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (200mg, 48.5% yield) as a white solid. MS (ESI) 300.1[ 2 ] M + H] + 。 1 H NMR(400MHz,CDCl 3 )δ7.60(d,J＝8.4Hz,1H),4.26-4.17(m,1H),3.86(q,J＝7.2Hz,2H),3.73-3.68(m,2H),3.63-3.58(m,1H),2.75-2.65(m,2H),2.61(s,3H),1.43(t,J＝7.2Hz,3H)。
Step 9) (E) -4- (3-chloro-6-ethoxy-2-fluoro-5- (1- (hydroxyimino) ethyl) phenyl) pyrrolidin-2-one
To a solution of 4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (50mg, 0.17mmol) and pyridine (26mg, 0.33mmol) in EtOH (20 mL) was added NH 2 OH.HCl (13mg, 0.18mmol) and the mixture was heated at 70 ℃ for 16h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL. Times.2). The separated organic layer was washed with Na 2 SO 4 Drying and concentration in vacuo afforded (E) -4- (3-chloro-6-ethoxy-2-fluoro-5- (1- (hydroxyimino) ethyl) phenyl) pyrrolidin-2-one (50mg, 85% yield) as a yellow solid. MS (ESI) 315.0[ m ] +H] + 。
Step 10) 4- (3- (1-aminoethyl) -2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
(E) -4- (3-chloro-6-ethoxy-2-fluoro-5- (1- (hydroxyimino) ethyl) phenyl) pyrrolidin-2-one (50mg, 0.16mmol) and Ni (9mg, 0.16mmol) in MeOH (20 mL) and NH 3 .H 2 O (2 mL) for H 2 The spheres were hydrogenated and the mixture was stirred at 25 ℃ for 16 hours. Filtration and concentration of the filtrate in vacuo gave 4- (3- (1-aminoethyl) -2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (40mg, 67% yield) as an off-white solid. MS (ESI) 250.1[ 2 ] M-NH 3 +H] + 。
Step 11) 4- (3- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
A solution of 4- (3- (1-aminoethyl) -2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (40mg, 0.13mmol), 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (28mg, 0.13mmol) and DIEA (34mg, 0.27mmol) in 2-pentanol (5 mL) was heated at 80 ℃ for 16h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was diluted with EtOAc (50 mL). The mixture was washed with brine (30mL. Times.2) and the organic layer was washed with Na 2 SO 4 Drying and concentrating. The residue was subjected to preparative HPLC (ACN-H) 2 O0.1 FA, gradient 30% to 60%) to give 4- (3- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (25mg, 39% yield) as a white solid. MS (ESI) 442.2[ m ] +H] + 。 1 H NMR(400MHz,DMSO)δ8.66(d,J＝7.2Hz,1H),8.01(d,J＝1.6Hz,1H),7.80(s,1H),7.64-7.42(m,2H),7.34-7.28(m,1H),7.04-6.98(m,1H),5.68-5.61(m,1H),4.10-3.98(m,2H),3.88-3.82(m,1H),3.62-3.51(m,1H),3.31-3.24(m,1H),2.58-2.54(m,1H),2.44(s,3H),2.38-2.31(m,1H),1.46(d,J＝6.8Hz,3H),1.41(t,J＝7.2,3H)。
Example 3- {3- [ (1S) -1- { [ 6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl ] amino } ethyl ] -5-chloro-2-methoxy-6-methylphenyl } -N N-dimethylpyridine-2-carboxamide
Step 1) 4-bromo-N, N-dimethylpyridine-2-carboxamide
To a mixture of 4-bromopyridine-2-carboxylic acid (1.1g, 5.40mmol), dimethylamine (0.66g, 8.10mmol) in DCM (15 mL) were added HATU (3.08g, 8.10mmol) and DIEA (1.4g, 10.8mmol), and the mixture was stirred at room temperature for 5 hours. LCMS showed reaction completion. The mixture was diluted with water (60 mL) and the mixture was extracted with DCM (30 mL. Times.3). The combined organic layers were washed with brine (20mL. Times.4) and Na 2 SO 4 Drying, and concentrating under reduced pressure. The residue was purified by flash chromatography (PE: EA = 2/1) to give 4-bromo-N, N-lutidine-2-carboxamide (1.10 g,70.7% yield) as a white solid. MS (ES)I):229.9[M+H] + 。
Step 2) N N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2-carboxamide
To a solution of 4-bromo-N, N-lutidine-2-carboxamide (1.0g, 4.4mmol) in dioxane (15 mL) was added 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolan (1.34g, 5.2mmol), pd (dppf) Cl at room temperature 2 (0.32g, 0.4mmol) and KOAc (1.30g, 13.2mol). The mixture was stirred at 80 ℃ for 6h. LCMS showed the product obtained. The solution was concentrated in vacuo to give N N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2-carboxamide (1.10 g,63.6% yield) as a black oil, which was used directly in the next step. MS (ESI) 299.1[ deg. ] M + Na ]] + 。
Step 3) 1- (5-chloro-2-hydroxy-3-iodo-4-methylphenyl) ethanone
To a solution of 1- (5-chloro-2-hydroxy-4-methylphenyl) ethanone (0.9g, 4.9mmol) in HOAc (15 mL) was added NIS (1.64g, 7.3mmol) at room temperature. The mixture was stirred at 80 ℃ for 16h. LCMS showed the major peak as product. Saturated Na for reaction 2 SO 3 Aqueous solution (10 mL) was quenched. The solution was concentrated in vacuo and extracted with DCM (50 mL. Times.3). The organic layer was washed with brine (50mL x 3) and Na 2 SO 4 Drying, and concentrating under reduced pressure. The residue was purified by silica gel column (200-300 mesh, PE: EA = 1:1) to give 1- (5-chloro-2-hydroxy-3-iodo-4-methylphenyl) ethanone (1.1g, 73.3% yield) as a yellow oil. MS (ESI) 311.8[ 2 ] M + H] + 。
Step 4) 1- (5-chloro-3-iodo-2-methoxy-4-methylphenyl) ethanone
To a solution of 1- (5-chloro-2-hydroxy-3-iodo-4-methylphenyl) ethanone (1.1g, 3.5 mmol) in DMF (15 mL) at room temperature were added MeI (1.51g, 10.5 mmol) and K 2 CO 3 (0.98g, 7.0 mmol). The mixture was stirred at room temperature for 4 hours. LCMS showed reaction completion. The mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL. Times.3). The combined organic layers were washed with brine (50mL. Times.4) and Na 2 SO 4 Drying, and concentrating under reduced pressure. The residue was purified by silica gel column (200-300 mesh, PE: EA = 2:1)To give 1- (5-chloro-3-iodo-2-methoxy-4-methylphenyl) ethanone (0.90g, 78.2% yield) as a yellow oil. MS (ESI) 324.9[ 2 ] M + H] + 。
Step 5) 4- (3-acetyl-5-chloro-2-methoxy-6-methylphenyl) -N, N-dimethylpyridine-2-carboxamide
To a solution of 1- (5-chloro-3-iodo-2-methoxy-4-methylphenyl) ethanone (0.9g, 2.8mmol) in dioxane (40 mL) and H 2 To a solution of O (10 mL) were added N, N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2-carboxamide (1.16g, 4.2mmol), pd (dppf) Cl 2 (0.23g, 0.2mmol) and CS 2 CO 3 (1.82g, 5.6 mmol). Mixing the mixture in N 2 And stirred at 100 ℃ for 16 hours. LCMS showed the major peak as product. The mixture was concentrated in vacuo and then diluted with water (60 mL). The mixture was extracted with DCM (50mL × 3) and the combined organic layers were washed with brine (100mL × 2) and Na 2 SO 4 Drying, and concentrating under reduced pressure. The residue was purified by silica gel column (200-300 mesh, PE: EA = 2:1) to give 4- (3-acetyl-5-chloro-2-methoxy-6-methylphenyl) -N, N-lutidine-2-carboxamide (0.82g, 67.8% yield) as a white solid. MS (ESI) 347.0[ deg. ] M + H] + 。
Step 6) 4- { 3-chloro-5- [ (1E) -1- (hydroxyimino) ethyl ] -6-methoxy-2-methylphenyl } -N, N-dimethylpyridine-2-carboxamide
To a solution of 4- (3-acetyl-5-chloro-2-methoxy-6-methylphenyl) -N, N-dimethylpyridine-2-carboxamide (100mg, 0.29mmol) in EtOH (5 mL) at room temperature was added NH 2 OH.HCl (30.0 mg, 0.43mmol) and pyridine (45.60mg, 0.58mmol). The mixture was heated at 70 ℃ for 8 hours. LCMS showed reaction completion. The mixture was concentrated in vacuo and diluted with water (30 mL). The solution was extracted with DCM (30mL x 3), and the combined organic layers were washed with brine (30mL x 3) and Na 2 SO 4 Drying, and concentrating under reduced pressure. The residue was purified by flash chromatography (200-300 mesh, PE: EA = 2:1) to give 4- { 3-chloro-5- [ (1E) -1- (hydroxyimino) ethyl]-6-methoxy-2-methylphenyl } -N, N-dimethylpyridine-2-carboxamide (80mg, 61.4% yield) as a clear oil. MS (ESI) 362.0[ m ] +H] + 。
Step 7) 4- [3- (1-aminoethyl) -5-chloro-2-methoxy-6-methylphenyl ] -N, N-dimethylpyridine-2-carboxamide
To 4- { 3-chloro-5- [ (1E) -1- (hydroxyimino) ethyl at room temperature]-6-methoxy-2-methylphenyl } -N, NH of N-lutidine-2-carboxamide (80mg, 0.22mmol) 3 .H 2 To a solution of O (5 mL) were added Raney nickel (50 mg) and thiophene (0.5 mL). The mixture is in H 2 The mixture was stirred at room temperature for 4 hours. LCMS showed reaction completion. Filtering, reacting, and vacuum concentrating the filtrate to obtain 4- [3- (1-aminoethyl) -5-chloro-2-methoxy-6-methylphenyl]-N, N-lutidine-2-carboxamide (70mg, 94.1% yield) was a clear oil. MS (ESI) 348.1[ deg. ] M + H] + 。
Step 8) 4- {3- [ (1S) -1- { [ 6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl ] amino } ethyl ] -5-chloro-2-methoxy-6-methylphenyl } -N N-dimethylpyridine-2-carboxamide
To 4- [3- (1-aminoethyl) -5-chloro-2-methoxy-6-methylphenyl ester at room temperature]To a solution of-N, N-lutidine-2-carboxamide (75mg, 0.25mmol) in 2-pentanol (5 mL) was added 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (50.20mg, 0.24mmol) and DIEA (41.70mg, 0.32mmol). The mixture was heated at 90 ℃ for 4 hours. LCMS showed reaction completion. After cooling to room temperature, the solution was diluted with water (50 mL) and then extracted with DCM (30 mL. Times.3). The combined organic layers were washed with brine (30mL. Times.3) and Na 2 SO 4 Drying, and concentrating under reduced pressure. The residue was subjected to preparative HPLC (ACN- -H) 2 O (0.1% FA) gradient: 40-60%) to yield 4- {3- [ (1S) -1- { [ 6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl]Amino } ethyl group]-5-chloro-2-methoxy-6-methylphenyl } -N N-dimethylpyridine-2-carboxamide (28.6mg, 25.4% yield) as a white solid. MS (ESI) 522.8[ 2 ] M + H] + 。 1 H NMR(400MHz,DMSO)δ8.71(dd,J＝16.2,6.1Hz,2H),8.02(s,1H),7.55-7.37(m,4H),5.6-5.57(m,1H),3.38(s,3H),3.03(s,3H),2.96(s,3H),2.46(s,3H),2.04(s,3H),1.52(d,J＝6.9Hz,3H)。
Example 4- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -6-chloro-3-ethoxy-2- (5-oxopyrrolidin-3-yl) benzonitrile
Step 1) 4-acetyl-6-chloro-3-ethoxy-2- (5-oxopyrrolidin-3-yl) benzonitrile
To a solution of 4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (200mg, 0.567 mmol) in DMSO (10 mL) was added NaCN (49mg, 1mmol) and the mixture was heated at 80 ℃ for 3h. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL. Times.3). The combined organic layers were washed with brine (30mL. Times.2) and Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by silica gel chromatography (EA/PE = 2/1) to give 4-acetyl-6-chloro-3-ethoxy-2- (5-oxopyrrolidin-3-yl) benzonitrile (110mg, 46.4% yield) as a yellow solid. MS (ESI) 307.0[ m ] +H] + 。 1 H NMR(400MHz,CDCl 3 )δ7.49(s,1H),5.87(s,1H),4.44-4.34(m,1H),3.87(q,J＝7.2Hz,2H),3.88-3.68(m,2H),2.85-2.61(m,2H),2.61(s,3H),1.43(t,J＝7.2Hz,3H)。
Step 2) (E) -6-chloro-3-ethoxy-4- (1- (hydroxyimino) ethyl) -2- (5-oxopyrrolidin-3-yl) benzonitrile
To a solution of 4-acetyl-6-chloro-3-ethoxy-2- (5-oxopyrrolidin-3-yl) benzonitrile (110mg, 0.36mmol) and pyridine (57mg, 0.71mmol) in EtOH (20 mL) was added NH 2 OH.HCl (27mg, 0.39mmol), and the mixture was heated at 60 ℃ for 16h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was diluted with EtOAc (50 mL). The mixture was washed with brine (30mL. Times.2) and the separated organic layer was washed with Na 2 SO 4 Drying and concentration gave (E) -6-chloro-3-ethoxy-4- (1- (hydroxyimino) ethyl) -2- (5-oxopyrrolidin-3-yl) benzonitrile (90mg, 70% yield) as a yellow solid. MS (ESI) 322.1[ 2 ] M + H] + 。 1 H NMR(400MHz,CDCl 3 )δ13.44(d,J＝2.0Hz,1H),7.83(d,J＝8.0Hz,1H),2.66(s,3H)。
Step 3) 4- (1-aminoethyl) -6-chloro-3-ethoxy-2- (5-oxopyrrolidin-3-yl) benzonitrile
Reacting (E) -6-chloro-3-ethoxy-4- (1- (hydroxyimino) ethyl) -2- (5-oxopyrrolidine-3-yl) benzonitrile (40mg, 0.12mmol), a mixture of Ni (5 mg) and thiophene (21mg, 0.25mmol) in MeOH (30 mL) and NH 3 H 2 A solution of O (1 mL) was hydrogenated at 25 ℃ for 16h. The mixture was then filtered and the filtrate was concentrated in vacuo to give 4- (1-aminoethyl) -6-chloro-3-ethoxy-2- (5-oxopyrrolidin-3-yl) benzonitrile (30mg, 70.6% yield) as a yellow solid. MS (ESI) 307.8[ 2 ] M + H] + 。
Step 4) 4- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -6-chloro-3-ethoxy-2- (5-oxopyrrolidin-3-yl) benzonitrile
A solution of 4- (1-aminoethyl) -6-chloro-3-ethoxy-2- (5-oxopyrrolidin-3-yl) benzonitrile (30mg, 0.1mmol), 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (21mg, 0.1mmol) and DIEA (25mg, 0.19mmol) in 2-pentanol (5 mL) was heated at 90 deg.C for 16h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was diluted with EtOAc (40 mL). The mixture was washed with brine (30mL. Times.2) and the separated organic layer was washed with Na 2 SO 4 Drying and vacuum concentrating. The residue was subjected to preparative HPLC (ACN-H) 2 O0.1 FA, gradient 20% to 50%) to give 4- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -6-chloro-3-ethoxy-2- (5-oxopyrrolidin-3-yl) benzonitrile (10.1mg, 20% yield) as a white solid. MS (ESI) 483.1[ 2 ] M + H] + 。 1 H NMR(400MHz,DMSO)δ8.50(d,J＝6.4Hz,1H),7.99-7.93(m,2H),7.79-7.65(m,2H),7.60(d,J＝3.6Hz,1H),5.57-5.53(m,1H),4.32-4.22(m,2H),3.92-3.88(m,1H),3.69-3.61(m,1H),3.51-3.44(m,1H),2.61-2.57(m,2H),2.46(s,3H),1.49(d,J＝4.8Hz,3H),1.44(t,J＝6.8Hz,3H)。
Example 5- (3- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one
Step 1) 1- (5-chloro-2-hydroxy-3-iodo-4-methylphenyl) ethan-1-one
To 1- (5-chloro-2-hydroxy)To a solution of 4-methylphenyl) ethan-1-one in acetic acid (15 mL) was added NIS (3.48g, 15.5 mmol) and the mixture was heated to 80 ℃ for 16h. Cooling to room temperature, adding Na 2 SO 3 (10 mL) quench. The mixture was concentrated and extracted 3 times with DCM (50mL × 3). The organic phases were combined, washed three times with saturated brine (50mL x 3), dried over anhydrous sodium sulfate, concentrated and the residue purified by silica gel chromatography (PE: EA = 3:1) to give 1- (5-chloro-2-hydroxy-3-iodo-4-methylphenyl) ethan-1-one (2.5 g,76.0% yield) as a yellow liquid. MS (ESI) 310.9[ 2 ] M + H] + . Step 2) 1- (5-chloro-2-ethoxy-3-iodo-4-methylphenyl) ethan-1-one
To a solution of 1- (5-chloro-2-hydroxy-3-iodo-4-methylphenyl) ethan-1-one (1.5 g, 4.80mmol) in DMF (10 mL) were added iodoethane (1.12g, 7.20mmol) and K 2 CO 3 (1.33g, 9.60mmol) and the mixture was warmed to 60 ℃ and stirred for 16h. The mixture was diluted with water (80 mL) and extracted three times with DCM (50mL. Times.3). The combined organic phases were washed four times with saturated brine (30mL. Times.4) over anhydrous Na 2 SO 4 Dried, concentrated and the residue purified by silica gel chromatography (PE: EA = 3:1) to give 1- (5-chloro-2-ethoxy-3-iodo-4-methylphenyl) ethan-1-one (1.55g, 95.0% yield) as a yellow liquid. MS (ESI) 338.6[ 2 ] M + H] + 。
Step 3) 2- (5-chloro-2-ethoxy-3-iodo-4-methylphenyl) -2-methyl-1,3-dioxolane
To a solution of 1- (5-chloro-2-ethoxy-3-iodo-4-methylphenyl) ethan-1-one in toluene (50 mL) was added ethylene glycol (0.57g, 9.2mmol) and PTSA (0.08g, 0.4 mmol), the mixture was stirred for 24h while warming to 130 ℃ under nitrogen. Cooled to room temperature, concentrated and the residue purified by column chromatography (PE: EA = 5:1) to give 2- (5-chloro-2-ethoxy-3-iodo-4-methylphenyl) -2-methyl-1,3-dioxolane (1.6 g,91.4 yield) as a clear oil. MS (ESI) 382.7[ 2 ] M + H] + 。
Step 4) Ethyl (E) -3- [ 3-chloro-6-ethoxy-2-methyl-5- (2-methyl-1,3-dioxolan-2-yl) phenyl ] acrylate
Ethyl 2- (5-chloro-2-ethoxy-3-iodo-4-methylphenyl) -2-methyl-1,3-dioxolane (1.6 g, 4.2mmol), ethyl acrylate (0.84g, 8.4 mmol), palladium acetate (0.09 g,0.4 mmol), tri-o-tolylphosphine (0.13g, 0.4mmol) and triethylamine (1.27g, 12.6 mmol) were added to DMA (5 mL), the mixture was blanketed with nitrogen and warmed to 90 ℃ and stirred for 16h. The mixture was diluted with water (80 mL) and extracted three times with DCM (50mL × 3). The combined organic phases were washed with saturated brine (30mL. Times.4) and anhydrous Na 2 SO 4 Dried, concentrated and the residue purified by column chromatography (PE: EA = 4:1) to give ethyl (E) -3- (3-chloro-6-ethoxy-2-methyl-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) acrylate (1.40g, 94.5% yield) as a yellow oil. MS (ESI) 354.9[ deg. ] M + H] + 。
Step 5) Ethyl 3- (3-chloro-6-ethoxy-2-methyl-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) -4-nitrobutanoate
Ethyl (E) -3- (3-chloro-6-ethoxy-2-methyl-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) acrylate (1.40g, 3.95mmol) in CH 3 NO 2 DBU (0.60g, 3.95mmol) was added to the solution (10 mL) and the mixture was stirred at 60 ℃ for 24h. The mixture was washed with water (80 mL), then extracted three times with DCM (30mL x 3), the organic phases were combined, washed three times with saturated brine (60mL x 3), over anhydrous Na 2 SO 4 Dried, concentrated and the residue purified by column chromatography (PE: EA = 3:1) to give ethyl 3- (3-chloro-6-ethoxy-2-methyl-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) -4-nitrobutanoate (0.58g, 35.3% yield) as a yellow oil. MS (ESI) 416.1[ 2 ] M + H] + 。
Step 6) 4- (3-chloro-6-ethoxy-2-methyl-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) pyrrolidin-2-one
A solution of ethyl 3- (3-chloro-6-ethoxy-2-methyl-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) -4-nitrobutanoate (0.6 g, 1.44mmol) and Raney nickel (200 mg) in methanol (10 mL) was hydrogenated with a hydrogen balloon, and the mixture was stirred at room temperature for 7h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (PE: EA = 1:1) to give 4- (3-chloro-6-ethoxy-2-methyl-5- (2-methyl-1,3-dioxolan-2-yl) phenyl) pyrrolidin-2-one (0.35g, 71.4% yield) as a clear oil. MS (ESI) 339.9[ 2 ] M + H] + 。
Step 7) 4- (3-acetyl-5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one
To 4- [ 3-chloro-6-ethoxy-2-methyl-5- (2-methyl-1,3-dioxolan-2-yl) phenyl]To a solution of pyrrolidin-2-one (0.35g, 1.04mmol) in MeOH (5 mL) was added 6N HCl (3 mL) and the mixture was stirred at 25 ℃ for 0.5h. The mixture was concentrated in vacuo to give 4- (3-acetyl-5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one (290mg, 95.4% yield) as a white solid. MS (ESI) 296.1[ deg. ] M + H] + 。
Step 8) 4- (3-chloro-6-ethoxy-5- ((1E) -1- (hydroxyimino) ethyl) -2-methylphenyl) pyrrolidin-2-one
To a solution of 4- (3-acetyl-5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one (100mg, 0.34mmol) and pyridine (53.49mg, 0.68mmol) in EtOH (10 mL) was added NH 2 OH.HCl (35.24mg, 0.51mmol), the mixture was warmed to 70 ℃ and stirred for 16h. After cooling to room temperature, the mixture was concentrated in vacuo, the residue was diluted with water (30 mL), then washed 3 times with DCM (30mL × 3), the organic phases were combined, washed three times with saturated brine (30mL × 3), over anhydrous Na 2 SO 4 Dried and then concentrated in vacuo, and the residue purified by silica gel chromatography (PE: EA = 2:1) to give 4- (3-chloro-6-ethoxy-5- ((1E) -1- (hydroxyimino) ethyl) -2-methylphenyl) pyrrolidin-2-one (102mg, 97.1% yield) as a clear liquid. MS (ESI) 311.1[ 2 ] M + H] + 。
Step 9) 4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one
4- (3-chloro-6-ethoxy-5- ((1E) -1- (hydroxyimino) ethyl) -2-methylphenyl) pyrrolidin-2-one (102mg, 0.33mmol), raney-Ni (50 mg), thiophene (0.5 mL) and NH 3 .H 2 Mixture of O (5 mL) in hydrogenation was carried out at 25 ℃ for 4h. The mixture was filtered and the filtrate was concentrated in vacuo to give 4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one (90mg, 92.4% yield) as a yellow oil. MS (ESI) 280.7[ deg. ] M + H] + 。
Step 10) 4- (3- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one
4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one (90mg, 0.30mmol), 2-pentanol (5 mL), 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (54.20mg, 0.26mmol) and DIEA were warmed to 90 ℃ and stirred for 4h. Cooled to room temperature, diluted with water (50 mL), then extracted with DCM (30mL x 3), the combined organic phases washed with saturated brine (30mL x 3), over anhydrous Na 2 SO 4 Drying, concentrating the mixture in vacuo, and subjecting the residue to preparative HPLC (ACN- -H) 2 Gradient of O (0.1% FA). 30% -50%) 4- (3- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one (46.5 mg,32.50% yield) was obtained as a white solid. MS (ESI) 471.9[ 2 ] M + H] + 。 1 H NMR(400MHz,DMSO)δ8.68(d,J＝5.4Hz,1H),8.04(s,1H),7.91(d,J＝3.3Hz,1H),7.35(d,J＝3.5Hz,1H),5.66-5.51(m,1H),4.37-4.25(m,1H),4.15-3.99(m,1H),3.85-3.68(m,1H),3.67-3.61(m,1H),3.34-3.14(m,2H),2.62-2.53(m,1H),2.45(s,3H),2.40-2.30(m,1H),2.25(d,J＝0.8Hz,3H),1.46(dd,J＝6.8,2.2Hz,3H),1.40(t,J＝6.8Hz,3H)。
Example 6- (3- (1- (6-amino-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
Step 1) 4,6-dichloropyrimidine-5-carbonyl chloride
To a solution of 4,6-dichloropyrimidine-5-carboxylic acid (950mg, 4.67mmol) and DMF (34mg, 0.47mmol) in dichloromethane (30 mL) was slowly dropped thionyl chloride (1.67g, 14mmol), and the mixture was stirred at 60 ℃ for 16 hours. The solution was concentrated under reduced pressure to give 4,6-dichloropyrimidine-5-carbonyl chloride (1g, 91.28%) as a yellow oil. MS (ESI) 210.9[ deg. ] M + H] + 。
Step 2) N' -acetyl-4,6-dichloropyrimidine-5-carbohydrazide
To a solution of acetohydrazide (1.5g, 20mmol) and DIEA (18g, 0.14mol) in DCM (80 mL) at room temperature was slowly added 4,6-dichloropyrimidineA solution of pyridine-5-carbonyl chloride (4.2g, 20mmol) in DCM (50 mL) was stirred at room temperature for 2 hours. The mixture was quenched with water (200 mL) and extracted with dichloromethane (300 mL), the combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (methanol: dichloromethane =1 20) to give N' -acetyl-4,6-dichloropyrimidine-5-carbohydrazide (350mg, 10.37% yield) as a yellow solid. MS (ESI) 248.8[ 2 ] M + H] + 。
Step 3) N' -acetyl-4-amino-6-chloropyrimidine-5-carbohydrazide
To a solution of N' -acetyl-4,6-dichloropyrimidine-5-carbohydrazide (350mg, 1.4 mmol) in 1,4-dioxane (50 mL) was added aqueous ammonia (10 mL), and the mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure and the concentrated solution was purified by silica gel chromatography (methanol/dichloromethane = 1/10) to give N' -acetyl-4-amino-6-chloropyrimidine-5-carbohydrazide (350mg, 97.62% yield) as a yellow solid. MS (ESI) 230.0[ m ] +H] + 。
Step 4) 6-chloro-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-amine
To a solution of N' -acetyl-4-amino-6-chloropyrimidine-5-carbohydrazide (325mg, 1.52mmol) in toluene (30 mL) at room temperature was added a Burgis reagent (726mg, 3.04mmol), and the mixture was stirred at 110 ℃ for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to give 6-chloro-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-amine (115mg, 33.87% yield) as a white solid. MS (ESI) 211.9[ deg. ] M + H] + 。
Step 5) 4- (3- (1- (6-amino-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (30mg, 0.1mmol), 6-chloro-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-amine (21mg, 0.1mmol) and N, N-diisopropylethylamine (26mg, 0.2mmol) were dissolved in 2-pentanol (10 mL) and the mixture was stirred at 90 ℃ for 9 h. Concentrating the solution under reduced pressure, adding ethyl acetateDiluted (30 mL), washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product is subjected to high-efficiency preparation of liquid phase (ACN-H) 2 O (0.1% FA) gradient 40% -60%) to give (4- (3- (1- (6-amino-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (11.3mg, 24% yield) as a white solid. MS (ESI) 476.1[ m ] +H] + 。 1 H NMR(400MHz,DMSO)δ8.42-8.37(m,1H),8.01(d,J＝2.6Hz,1H),7.84(s,1H),7.45-7.20(m,3H),5.64-5.57(m,1H),4.15-4.09(m,1H),4.06-4.00(m,1H),3.90-3.83(m,1H),3.65-3.58(m,1H),3.29-3.24(m,1H),2.59(s,3H),2.54(dd,J＝3.9,2.0Hz,1H),2.38-2.30(m,1H),1.48-1.38(m,6H)。
Example 7 (S) -4- (3- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-6-fluoro-2-methoxyphenyl) -N, N-dimethylpyridinamide
Step 1) 4-bromo-N, N-dimethylpyridine amide
To a solution of 4-bromopicolinic acid (796 mg, 3.94mmol) in dichloromethane (20 mL) were added dimethylamine hydrochloride (482mg, 5.91mmol), N-diisopropylethylamine (1.5g, 11.82mmol), and HATU (3g, 7.88mmol), and stirred at room temperature for 16 hours. The mixture was quenched with water (20 mL) and then extracted with dichloromethane (60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the crude product purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give 4-bromo-N, N-dimethylpyridine amide (630mg, 62.81% yield) as a yellow oil. MS (ESI) 230.9[ deg. ] M + H] + 。
Step 2) N, N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) picolinamide
To a solution of 4-bromo-N, N-dimethylpyridine amide (315mg, 1.38mmol) and bis-pinacolato borate (419mg, 1.65mmol) in dioxane (10 mL) was added anhydrous potassium acetate (405mg, 4.13mmol) and 1,1' -bis-diphenylphosphino ferrocene palladium dichloride(112mg, 0.14mmol) and the mixture was stirred at 80 ℃ for 16 hours. The mixture was concentrated in vacuo to give N, N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) picolinamide (265mg, 70% yield) as a yellow oil, which was used directly in the next reaction. MS (ESI) 195.0[ m ] +H] + 。
Step 3) 4- (3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl) -N, N-dimethylpyridine amide
To a solution of N, N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) picolinamide (265mg, 1.37mmol) and 1- (5-chloro-4-fluoro-3-iodo-2-methoxyphenyl) ethan-1-one (448.7mg, 1.37mmol) in dioxane (25 mL) and water (5 mL) was added potassium carbonate (565.5mg, 4.10mmol) and 1,1' -bis diphenylphosphinoferrocene dichloropalladium (111.5mg, 0.14mmol), and the mixture was stirred at 80 ℃ for 16 hours. The solution was concentrated under reduced pressure, diluted with ethyl acetate (200 mL), washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol = 97) to give 4- (3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl) -N, N-dimethylpyridinamide as a yellow oil (263mg, 49.4% yield). MS (ESI) 350.5[ deg. ] M + H] + 。
Step 4) (E) -4- (3-chloro-2-fluoro-5- (1- (hydroxyimino) ethyl) -6-methoxyphenyl) -N, N-dimethylpyridine amide
Pyridine (42mg, 0.53mmol) was added to a solution of 4- (3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl) -N, N-dimethylpyridinamide (62mg, 0.18mmol) and hydroxylamine hydrochloride (18.4mg, 0.27mmol) in ethanol (10 mL) under nitrogen, and stirred at 60 ℃ for 16 hours. The solution was concentrated under reduced pressure, diluted with ethyl acetate (30 mL), washed with saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave (E) -4- (3-chloro-2-fluoro-5- (1- (hydroxyimino) ethyl) -6-methoxyphenyl) -N, N-dimethylpyridine amide (60mg, 74.21% yield) as a yellow oil. MS (ESI) 366.0[ M ] +H] + 。
Step 5) 4- (3- (1-aminoethyl) -5-chloro-6-fluoro-2-methoxyphenyl) -N, N-dimethylpyridine amide
To (E) -4To a mixture of (3-chloro-2-fluoro-5- (1- (hydroxyimino) ethyl) -6-methoxyphenyl) -N, N-dimethylpyridinamide (58mg, 0.16mmol) and raney nickel (20 mg) in methanol (30 mL) were added aqueous ammonia (2ml, 20%) and thiophene (2 mL), and the mixture was stirred under hydrogen for 15 hours. The mixture was filtered and the filter cake was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure to give 4- (3- (1-aminoethyl) -5-chloro-6-fluoro-2-methoxyphenyl) -N, N-dimethylpyridinamide (55mg, 83.80% yield) as a yellow oil. MS (ESI) 351.9[ deg. ] M + H ]] + 。
Step 6) (S) -4- (3- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-6-fluoro-2-methoxyphenyl) -N, N-dimethylpyridinamide
To a solution of 4- (3- (1-aminoethyl) -5-chloro-6-fluoro-2-methoxyphenyl) -N, N-dimethylpyridinamide (46mg, 0.13mmol) and 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (28mg, 0.13mmol) in sec-amyl alcohol (10 mL) was added N, N-diisopropylethylamine (68mg, 0.52mmol) and the mixture was stirred at 90 ℃ for 9 h. The solution was concentrated under reduced pressure, diluted with dichloromethane (30 mL), washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product is subjected to high-efficiency preparation of liquid phase (ACN-H) 2 O (0.1% fa) gradient 30-70) to give (S) -4- (3- (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-6-fluoro-2-methoxyphenyl) -N, N-dimethylpyridinamide (8.7 mg,12.61% yield) as a white solid. MS (ESI) 527.8[ 2 ] M + H] + 。 1 H NMR(400MHz,DMSO)δ8.73(dd,J＝5.1,0.7Hz,1H),8.66(d,J＝7.2Hz,1H),8.00(s,1H),7.75-7.42(m,5H),5.62(dd,J＝14.0,7.0Hz,1H),3.45(s,3H),3.03(s,3H),2.97(s,3H),2.46(s,3H),1.54(d,J＝6.9Hz,3H)。
Example 8 (S) -4- (3- ((R) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
Step 1) (R) -4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
The 4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (1100.0 mg) synthesized in step 8 of example 1 was subjected to separation and purification by chiral column chromatography (method: SFC rear prep 80, column: CHIRALPAK IC mm. Times.20mm, 5 μm, eluent: 35% EtOH (NH) 4 OH 0.2%), flow rate: 40 g/min) gave (R) -4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (260.2 mg). MS (ESI) 300.1[ 2 ] M + H] + 。
Step 2) (R, E) -4- (3-chloro-6-ethoxy-2-fluoro-5- (1- (hydroxyimino) ethyl) phenyl) pyrrolidin-2-one
To a solution of (R) -4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (50.1mg, 0.17mmol) and pyridine (26.2mg, 0.33mmol) in EtOH (25 mL) was added NH 2 OH.HCl (13.8mg, 0.19mmol), and the mixture was heated at 70 ℃ for 18h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL. Times.2). The separated organic layer was washed with Na 2 SO 4 Drying and concentration in vacuo afforded (R, E) -4- (3-chloro-6-ethoxy-2-fluoro-5- (1- (hydroxyimino) ethyl) phenyl) pyrrolidin-2-one (50.9 mg,86.5% yield) as a yellow solid. MS (ESI) 315.0[ m ] +H] + 。
Step 3) (4R) -4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
To (R, E) -4- (3-chloro-6-ethoxy-2-fluoro-5- (1- (hydroxyimino) ethyl) phenyl) pyrrolidin-2-one (38mg, 0.12mmol), raney's nickel (10.1mg, 0.11mmol) and thiophene (13.6mg, 0.111mmol) in MeOH (10 mL) and NH 3 .H 2 The O (1.5 mL) mixture was hydrogenated at 25 ℃ for 16h. The mixture was then filtered and the filtrate was concentrated in vacuo to give (4R) -4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (26.5 mg,63.4% yield) as a white solid. MS (ESI) 283.9[ M-NH ] 3 +H] + 。
Step 4) (R) -4- (3- ((R) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
(4R) -4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (25.0 mg) was purified by filtrationChiral column chromatography separation and purification (method: SFC thumb 80, column: CHIRALPAK IC mm. Times.20mm, 5 μm, eluent: 40% EtOH (NH) 4 0.2% of OH), flow rate: 40 g/min) to give (R) -4- (3- ((R) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (10.1 mg).
Step 5) (S) -4- (3- ((R) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
A solution of (R) -4- (3- ((R) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (10.2mg, 0.03mmol), 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (7 mg, 0.03mmol) and DIEA (13.1mg, 0.1mmol) in 2-pentanol (5 mL) was heated at 90 ℃ for 20 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and washed with brine (20 mL. Times.2). The separated organic layer was washed with Na 2 SO 4 Drying and vacuum concentrating. The residue was subjected to preparative HPLC (ACN-H) 2 O0.1 FA, gradient 40% to 60%) to give (S) -4- (3- ((R) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (5.9 mg,34.8% yield) as a white solid. MS (ESI) 476.1[ m ] +H] + 。
Example 9 (R) -4- (3- ((R) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
Step 1) (S) -4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
The 4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (1100.0 mg) synthesized in step 8 of example 1 was subjected to separation and purification by chiral column chromatography (method: SFC rear prep 80, column: CHIRALPAK IC mm. Times.20mm, 5 μm, eluent: 35% EtOH (NH) 4 OH 0.2%), flow rate: 40 g/min) to give (S) -4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one(278.9mg)。MS(ESI):300.1[M+H] + 。
Step 2) (S, E) -4- (3-chloro-6-ethoxy-2-fluoro-5- (1- (hydroxyimino) ethyl) phenyl) pyrrolidin-2-one
To a solution of (S) -4- (3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (50.5mg, 0.18mmol) and pyridine (26.3mg, 0.33mmol) in EtOH (25 mL) was added NH 2 OH.HCl (13.7mg, 0.19mmol), and the mixture was heated at 70 ℃ for 16h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL. Times.2). The separated organic layer was washed with Na 2 SO 4 Drying and concentration in vacuo afforded (S, E) -4- (3-chloro-6-ethoxy-2-fluoro-5- (1- (hydroxyimino) ethyl) phenyl) pyrrolidin-2-one (56.1mg, 95.3% yield) as a yellow solid. MS (ESI) 315.0[ m ] +H] + 。
Step 3) (4S) -4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
To (S, E) -4- (3-chloro-6-ethoxy-2-fluoro-5- (1- (hydroxyimino) ethyl) phenyl) pyrrolidin-2-one (38.2mg, 0.12mmol), raney' S nickel (10.1mg, 0.11mmol) and thiophene (13.5mg, 0.111mmol) in MeOH (10 mL) and NH 3 .H 2 The O (1.5 mL) mixture was hydrogenated at 25 ℃ for 16h. The mixture was then filtered and the filtrate was concentrated in vacuo to give (4S) -4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (27.7 mg,66.3% yield) as a white solid. MS (ESI) 283.9[ 2 ] M-NH 3 +H] + 。
Step 4) (S) -4- (3- ((R) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
(4S) -4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (27.7 mg) was purified by chiral column chromatography (method: SFC rear prep 80, column: CHIRALPAK IC mm. Times.20mm, 5 μm, eluent: 40% EtOH (NH) 4 OH 0.2%), flow rate: 40 g/min) gave (S) -4- (3- ((R) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (16.1 mg).
Step 5) (R) -4- (3- ((R) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
Reacting (S) -4- (3- ((R) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (10.1mg, 0.03mmol) A solution of 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (7.0 mg, 0.03mmol) and DIEA (13.2 mg, 0.1mmol) in 2-pentanol (6.0 mL) was heated at 90 ℃ for 12 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and washed with brine (20 mL. Times.2). The separated organic layer was washed with Na 2 SO 4 Drying and vacuum concentrating. The residue was subjected to preparative HPLC (ACN-H) 2 O0.1 FA, gradient 40% to 60%) to give (R) -4- (3- ((R) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (5.5 mg,32.4% yield) as a white solid. MS (ESI) 476.1[ m ] +H] + 。
Example 10 (S) -4- (3- ((S) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
Step 1) (R) -4- (3- ((S) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
(4R) -4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (25.0 mg) was purified by chiral column chromatography (method: SFC rear prep 80, column: CHIRALPAK IC mm. Times.20mm, 5 μm, eluent: 40% EtOH (NH) 4 OH 0.2%), flow rate: 40 g/min) to give (R) -4- (3- ((S) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (12.7 mg).
Step 2) (S) -4- (3- ((S) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
(R) -4- (3- ((S) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (12.0mg, 0.03mmol), 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (10mg, 0.04mmol) anda solution of DIEA (13.2 mg,0.1 mmol) in 2-pentanol (6.0 mL) was heated at 90 ℃ for 12 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and washed with brine (20 mL. Times.2). The separated organic layer was passed over Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by preparative HPLC (ACN-H2O 0.1FA, gradient 40% to 60%) to give (S) -4- (3- ((S) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (7.3mg, 36.1% yield) as a white solid MS (ESI): 476.1[ M + H ])] + 。
Example 11 (R) -4- (3- ((S) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
Step 1) (S) -4- (3- ((S) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
(4S) -4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (27.7 mg) was purified by chiral column chromatography (method: SFC rear prep 80, column: CHIRALPAK IC mm. Times.20mm, 5 μm, eluent: 40% EtOH (NH) 4 OH 0.2%), flow rate: 40 g/min) gave (S) -4- (3- ((S) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (18.2 mg).
Step 2) (R) -4- (3- ((S) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
A solution of (S) -4- (3- ((S) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (15.0mg, 0.04mmol), 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (10.2mg, 0.04mmol), and DIEA (13.1mg, 0.1mmol) in 2-pentanol (6.0 mL) was heated at 90 ℃ for 19 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and washed with brine (20 mL. Times.2). The separated organic layer was washed with Na 2 SO 4 Drying and vacuumAnd (4) concentrating. The residue was subjected to preparative HPLC (ACN-H) 2 O0.1 FA, gradient 40% to 60%) to give (R) -4- (3- ((S) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (7.1mg, 28.4% yield) as a white solid. MS (ESI) 476.1[ m ] +H] + 。
Example 12- (3- ((R) 1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one
Step 1) 4- (3 ((R) - (1-aminoethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one
4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one (150.0 mg) was purified by chiral column chromatography (method: SFC rear prep 80, column: CHIRALPAK IC mm. Times.20mm, 5 μm, eluent: 40% EtOH (NH) 4 OH 0.2%), flow rate: 40 g/min) to give 4- (3 ((R) - (1-aminoethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one (38.9 mg).
Step 2) 4- (3- ((R) 1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one
A solution of 4- (3 ((R) - (1-aminoethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one (35.0mg, 0.12mmol), 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (28.1mg, 0.12mmol), and DIEA (26.5mg, 0.2mmol) in 2-pentanol (5.0 mL) was heated at 90 ℃ for 19 hours, after cooling to room temperature, the mixture was concentrated in vacuo, the residue was diluted with EtOAc (30 mL), then washed with brine (20 mL. Times.2), and the separated organic layer was Na-doped 2 SO 4 Drying and vacuum concentrating. The residue was subjected to preparative HPLC (ACN-H) 2 O0.1 FA, gradient 40% to 60%) to give (S) -4- (3- ((R) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (22)2mg,40.1% yield) as a white solid. MS (ESI) 471.9[ 2 ] M + H] + 。
Example 13- (3- ((S) 1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one
Step 1) 4- (3 ((S) - (1-aminoethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one
4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one (150.0 mg) was purified by chiral column chromatography (method: SFC rear prep 80, column: CHIRALPAK IC mm. Times.20mm, 5 μm, eluent: 40% EtOH (NH) 4 OH 0.2%), flow rate: 40 g/min) to give 4- (3 ((S) - (1-aminoethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one (39.6 mg).
Step 2) 4- (3- ((S) 1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one
A solution of 4- (3 ((S) - (1-aminoethyl) -5-chloro-2-ethoxy-6-methylphenyl) pyrrolidin-2-one (35.1mg, 0.12mmol), 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (28.5mg, 0.12mmol), and DIEA (26.1mg, 0.2mmol) in 2-pentanol (5.0 mL) was heated at 90 ℃ for 19 hours, after cooling to room temperature, the mixture was concentrated in vacuo, the residue was diluted with EtOAc (30 mL) and then washed with brine (20 mL. Times.2). The separated organic layer was Na 2 SO 4 Drying and vacuum concentrating. The residue was subjected to preparative HPLC (ACN-H) 2 O0.1 FA, gradient 40% to 60%) to give (S) -4- (3- ((S) - (1- ((6-amino-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (20.1mg, 36.3% yield) as a white solid. MS (ESI) 471.9[ 2 ] M + H] + 。
Example 14 (S) -4- (3- ((R) -1- (6-amino-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
A solution of (R) -4- (3- ((R) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (10.1mg, 0.03mmol), 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (7.1mg, 0.03mmol) and DIEA (15.6mg, 0.12mmol) in 2-pentanol (5.0 mL) was heated at 80 ℃ for 24 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and washed with brine (20 mL. Times.2). The separated organic layer was washed with Na 2 SO 4 Drying and vacuum concentrating. The residue was subjected to preparative HPLC (ACN-H) 2 O0.1 FA, gradient 40% to 60%) to give (S) -4- (3- ((R) -1- (6-amino-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (4.7 mg,30.1% yield) as a white solid. MS (ESI) 476.1[ m ] +H] + 。
Example 15 (S) -4- (3- ((S) -1- (6-amino-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
A solution of (R) -4- (3- ((S) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (15.1mg, 0.04mmol), 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (10.5mg, 0.04mmol) and DIEA (16.8mg, 0.13mmol) in 2-pentanol (5.0 mL) was heated at 90 ℃ for 16 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and washed with brine (20 mL. Times.2). The separated organic layer was washed with Na 2 SO 4 Drying and vacuum concentrating. The residue was subjected to preparative HPLC (ACN-H) 2 O0.1 FA, gradient 40% to 60%) to give (S) -4- (3- ((S) -1- (6-amino-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (4.7 mg,32.8% yield) as yellowA colored solid. MS (ESI) 476.1[ m ] +H] + 。
Example 16 (R) -4- (3- ((R) -1- (6-amino-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
A solution of (S) -4- (3- ((R) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (12.6 mg, 0.04mmol), 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (8.8mg, 0.04mmol) and DIEA (15.3mg, 0.12mmol) in 2-pentanol (6.0 mL) was heated at 90 ℃ for 12 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (10 mL) and washed with brine (10 mL. Times.2). The separated organic layer was washed with Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by preparative HPLC (ACN-H2O 0.1FA, gradient 40% to 60%) to give (R) -4- (3- ((R) -1- (6-amino-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (6.3mg, 31.8% yield) as a white solid. MS (ESI) 476.1[ m ] +H] + 。
Example 17 (R) -4- (3- ((S) -1- (6-amino-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
A solution of (S) -4- (3- ((R) -1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (10.6 mg, 0.03mmol), 6-chloro-5- (3-methyl-1,2,4-oxadiazol-5-yl) pyrimidin-4-amine (7.2mg, 0.03mmol) and DIEA (13.5mg, 0.1mmol) in 2-pentanol (6.0 mL) was heated at 90 ℃ for 12 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (10 mL) and washed with brine (10 mL. Times.2). The separated organic layer was washed with Na 2 SO 4 Drying and vacuum concentrating. The residue was subjected to preparative HPLC (ACN-H) 2 O 0.1FA，Gradient 40% to 60%) to give (R) -4- (3- ((S) -1- (6-amino-5- (5-methyl-1,3,4-oxadiazol-2-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (7.1mg, 42.7% yield) as a white solid. MS (ESI) 476.1[ m ] +H] + 。
Example 18 (R) -4- (3- ((S) 1- ((6-amino-5- (2-methyl-2H-tetrazolyl-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
Step 1) 5-iodo-2-methyl-2H-tetrazole
To 2-methyl-1,2,3,4-tetrazolyl-5-amine (5g, 50.5mmol), cuprous iodide (9.62g, 50.5mmol) and CH 2 I 2 To a solution of (68g, 0.25mol) in THF (50 mL) was added isoamyl nitrite (21.3 g, 0.18mol), and the mixture was stirred at 60 ℃ for 2 hours. Cooled to room temperature and the mixture was diluted with EtOAc (100 mL) and washed with saturated brine (60mL. Times.2). The organic phase is passed through Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by column chromatography (EA/PE = 1/10) to give 5-iodo-2-methyl-2H-tetrazole (3.6g, 32.3% yield) as a white solid. MS (ESI) 210.8[ 2 ] M + H] + 。
Step 2) 2-methyl-5- (tert-butyltin) -2H-tetrazole
To a solution of 5-iodo-2-methyl-2H-tetrazole (2.0 g,9.5 mmol) in THF (30 mL) at-78 deg.C, n-butyllithium (5.9mL, 14mmol) was slowly added dropwise, and stirring was continued for 1H. Then add (n-Bu) 3 SnCl (4.64g, 14.25mmol), and the mixture was warmed to 25 deg.C and stirred for 4h. Then using NH 4 Aqueous Cl (50 mL) was quenched and extracted with EtOAc (50mL. Times.3). The combined organic phases were washed with brine (40mL. Times.2) and anhydrous Na 2 SO 4 Dried, concentrated in vacuo and the residue purified by column chromatography (PE/EA = 20/1) to give 2-methyl-5- (tert-butyltin) -2H-tetrazole (2.58g, 65.2% yield) as a yellow oil. MS (ESI) 374.9[ 2 ], [ M ] +H] + 。
Step 3) 4,6-dimethoxy-5- (2-methyl-2H-tetrazolyl-5-yl) pyrimidine
To a solution of 5-bromo-4,6-dimethoxypyrimidine (500mg, 2.28mmol) in DMF (20 mL) was added 2-methyl-5- (tri-tert-butyltin) -2H-tetrazole (1.7 g, 4.57mmol) and Pd (dppf) Cl 2 (370mg, 0.46mmol), the mixture is stirred for 24h at 120 ℃. Cool to room temperature then concentrate in vacuo and the residue is diluted with water (50 mL) then extracted with EtOAc (50mL × 3). The combined organic phases were washed with saturated brine (40mL. Times.2) over anhydrous Na 2 SO 4 Drying and vacuum concentrating. The residue was purified by column chromatography (PE/EA = 2/1) to give 4,6-dimethoxy-5- (2-methyl-2H-tetrazolyl-5-yl) pyrimidine (310mg, 58% yield) as a yellow oil. MS (ESI) 223.0[ m ] +H] + 。
Step 4) 4,6-dihydroxy-5- (2) -methyl-2H-tetrazolyl-5-yl) pyrimidine
To a solution of 4,6-dimethoxy-5- (2-methyl-2H-tetrazol-5-yl) pyrimidine (310mg, 1.40mmol) in AcOH (10 mL) was added concentrated hydrochloric acid (2.0 mL), the mixture was warmed to 100 ℃ and stirred for 5H. Cooled to room temperature and concentrated in vacuo to afford 4,6-dihydroxy-5- (2-methyl-2H-tetrazol-5-yl) pyrimidine (280mg, 93% yield) as a yellow solid. MS (ESI) 195.1[ deg. ] M + H] + 。
Step 5) 4,6-dichloro-5- (2-methyl-2H-tetrazolyl-5-yl) pyrimidine
4,6-dihydroxy-5- (2-methyl-2H-tetrazol-5-yl) pyrimidine (40mg, 0.21mmol) was dissolved in POCl 3 (5 mL) DIEA (80mg, 0.62mmol) was then added and the mixture was stirred for 5h at 100 ℃. Cooled to room temperature, concentrated in vacuo and the residue taken up in H 2 O (20 mL) was diluted and then extracted with EtOAc (30mL x 3). The combined organic phases were washed with saturated brine (50mL. Times.2) over anhydrous Na 2 SO 4 Dried and concentrated in vacuo to afford 4,6-dichloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidine (50mg, 94.56% yield) as a yellow solid. MS (ESI) 230.9[ deg. ] M + H] + 。
Step 6) 6-chloro-5- (2-methyl-2H-tetrazolyl-5-yl) pyrimidin-4-amine
At the temperature of 0 ℃, the temperature of the mixture is controlled, to a solution of 4,6-dichloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidine (40mg, 0.17mmol) in dioxane (10 mL) was added NH 3 .H 2 O (73mg, 0.52mmol), and the temperature is raised to 25 ℃ and stirred for 16h. Then concentrated in vacuo and the residue diluted with EtOAc (100 mL) and washed with brine (40mL. Times.2). The separated organic phase is passed through anhydrous Na 2 SO 4 Drying and concentration in vacuo afforded 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (37mg, 90.93% yield) as a yellow solid. MS (ESI) 212.0[ 2 ] M + H] + 。
Step 7) 4- (3- (1- ((6-amino-5- (2-methyl-2H-tetrazolyl-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
To a solution of 6-chloro-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-amine (36mg, 0.17mmol) in 2-pentanol (20 mL) was added 4- (3- (1-aminoethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (51.16mg, 0.17mmol) and DIEA (66mg, 0.51mmol), and the mixture was stirred at 100 ℃ for 18H. Cool to room temperature, concentrate in vacuo, dilute the residue with water (20 mL), and extract with EtOAc (30mL × 3). The combined organic phases were washed with saturated brine (50mL. Times.2) and then over anhydrous Na 2 SO 4 Drying, vacuum concentrating, and subjecting the residue to high performance preparative liquid phase separation (-Gemini-C18 150x21.2mm,5um ACN- -H 2 O (0.1% FA), 15% -50%) and chiral high performance preparative chromatography (chiralpak-AD, CO) 2 MeOH (DEA)) to give (R) -4- (3- ((S) 1- ((6-amino-5- (2-methyl-2H-tetrazolyl-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (3.6 mg) and (R) -4- (3- ((R) 1- ((6-amino-5- (2-methyl-2H-tetrazolyl-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one (3.0 mg) as a white solid.
(R) -4- (3- ((S) 1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one: MS (ESI) 475.9[ 2 ] M + H] + . 1 H NMR(400MHz,DMSO)δ8.45(d,J＝7.1Hz,1H),7.97(s,1H),7.84(s,1H),7.45(s,2H),7.39(d,J＝8.4Hz,1H),5.62(q,J＝7.0Hz,1H),4.50(s,3H),4.18(dq,J＝13.8,6.9Hz,1H),4.04(dt,J＝18.0,9.0Hz,1H),3.87(dq,J＝14.1,7.0Hz,1H),3.64(t,J＝9.4Hz,1H),3.29(s,1H),2.59-2.52(m,1H),2.30(dd,J＝17.3,8.1Hz,1H),1.48(d,J＝6.8Hz,3H),1.42(t,J＝7.0Hz,3H)。
Example 19 (R) -4- (3- ((R) 1- ((6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one
(R) -4- (3- ((R) 1- ((6-amino-5- (2-methyl-2H-)) tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -5-chloro-2-ethoxy-6-fluorophenyl) pyrrolidin-2-one: MS (ESI) 475.8[ 2 ] M + H] + 。 1 H NMR(400MHz,DMSO)δ8.45(d,J＝7.2Hz,1H),7.98(s,1H),7.84(s,1H),7.45(s,2H),7.39(d,J＝8.4Hz,1H),5.67-5.56(m,1H),4.50(s,3H),4.16(dt,J＝14.2,7.0Hz,1H),4.03(dd,J＝17.7,8.8Hz,1H),3.95-3.85(m,1H),3.58(t,J＝9.8Hz,1H),3.29-3.23(m,1H),2.59(dd,J＝17.7,9.4Hz,1H),2.37(dd,J＝17.5,8.8Hz,1H),1.48(d,J＝6.9Hz,3H),1.42(t,J＝6.9Hz,3H)。
Biological assay
Kinase activity assay the activity of the compounds of the invention as PI3K and mTOR kinase inhibitors can be assessed by the following assay. General description of kinase assays are performed by detecting Myelin Basic Protein (MBP) that incorporates gamma-33P-ATP. mu.g/mL of MBP (Sigma # M-1891) Tris buffered saline (TBS; 50mM Tris pH 8.0,138mM NaCl,2.7mM KCl) was prepared, coated in high binding white 384 well plates (Greiner) at 60. Mu.L per well. Incubate at 4 ℃ for 24 hours. The plate was then washed 3 times with 100. Mu.L TBS. Kinase reaction in a total volume of 34. Mu.L of kinase buffer (5 mM Hepes pH 7.6,15mM NaCl,0.01% bovine serum albumin (Sigma # I-5506), 10mM MgCl 2 1mM DTT,0.02% TritonX-100). Compounds were dissolved in DMSO and added to each well at a final DMSO concentration of 1%. Each data was assayed in two passes, with at least two trials for each compound assay. For example, the final concentration of the enzyme is 10nM or 20nM. The reaction was started by adding unlabeled ATP (10. Mu.M) and gamma-33P-labeled ATP (2X 106cpm per well, 3000 Ci/mmole). The reaction was performed at room temperature with shaking for 1 hour. The 384 well plates were washed with 7x PBS and then 50 μ L scintillation fluid per well was added. By usingA Wallac Trilux meter is also possible.
The above test methods result in an inhibitory IC50 and/or an inhibitory constant Ki. IC50 is defined as the concentration of compound that inhibits 50% of the enzyme activity under the conditions tested. IC was estimated by making a curve containing 10 concentration points using 1/2log dilution 50 Values (e.g., a typical curve is made by the concentration of compounds at 10. Mu.M, 3. Mu.M, 1. Mu.M, 0.3. Mu.M, 0.1. Mu.M, 0.03. Mu.M, 0.01. Mu.M, 0.003. Mu.M, 0.001. Mu.M and 0. Mu.M).
General assay protocol for PI3 kinase
PI3K (p 110. Alpha./p 85. Alpha.) (h) [ non-radioactive assay]
PI3K (p 110. Alpha./p 85. Alpha.) (h) in a medium containing 10. Mu.M phosphoinositide-4,5 incubation in a buffered solution of diphosphate and MgATP (concentrations determined as required). After addition of ATP solution, the reaction was started. After incubation at room temperature for 30 minutes, a stop solution containing EDTA and biotin phosphatidylinositol-3,4,5-triphosphate was added thereto to stop the reaction. Finally, a detection buffer comprising europium-labeled anti-GST monoclonal antibody, GST-labeled GRP1PH domain and streptavidin-allophycocyanin was added. The plates were read in time-resolved fluorescence mode and homogeneous time-resolved fluorescence (HTRF) signal was determined by the equation HTRF =10000 × (Em 665 nm/Em620 nm).
PI3K (p 110. Beta./p 85. Alpha.) (h) [ non-radioactive assay]
PI3K (p 110. Beta./p 85. Alpha.) (h) was incubated in a buffer solution containing 10. Mu.M phosphoinositide-4,5-diphosphate and MgATP (concentration determined as required). After addition of ATP solution, the reaction was started. After incubation at room temperature for 30 minutes, a stop solution containing EDTA and biotin phosphatidylinositol-3,4,5-triphosphate was added thereto to stop the reaction. Finally, a detection buffer comprising europium-labeled anti-GST monoclonal antibody, GST-labeled GRP1PH domain and streptavidin-allophycocyanin was added. The plates were read in time resolved fluorescence mode and Homogeneous Time Resolved Fluorescence (HTRF) signals were determined by the equation HTRF =10000 × (Em 665 nm/Em620 nm).
PI3K (p 110 delta/p 85 alpha) (h) [ non-radioactive test]
PI3K (p 110. Delta./p 85. Alpha.) (h) was incubated in a buffer solution containing 10. Mu.M phosphoinositide-4,5-diphosphate and MgATP (concentration determined as required). After addition of ATP solution, the reaction was started. After incubation at room temperature for 30 minutes, a stop solution containing EDTA and biotin phosphatidylinositol-3,4,5-triphosphate was added thereto to stop the reaction. Finally, a detection buffer solution comprising europium-labeled anti-GST monoclonal antibody, GST-labeled GRP1PH domain and streptavidin-allophycocyanin is added. The plates were read in time-resolved fluorescence mode and homogeneous time-resolved fluorescence (HTRF) signal was determined by the equation HTRF =10000 × (Em 665 nm/Em620 nm).
PI3K (p 120. Gamma.) (h) [ non-radioactive assay]
PI3K (p 120. Gamma.) (h) was incubated in a buffer solution containing 10. Mu.M phosphoinositide-4,5-diphosphate and MgATP (concentration determined as required). After addition of ATP solution, the reaction was started. After incubation at room temperature for 30 minutes, a stop solution containing EDTA and biotin phosphatidylinositol-3,4,5-triphosphate was added thereto to stop the reaction. Finally, a detection buffer comprising europium-labeled anti-GST monoclonal antibody, GST-labeled GRP1PH domain and streptavidin-allophycocyanin was added. The plates were read in time-resolved fluorescence mode and homogeneous time-resolved fluorescence (HTRF) signal was determined by the equation HTRF =10000 × (Em 665 nm/Em620 nm).
The kinase assay in the present invention was performed by Eurofins Inc. of France (Eurofins Cerep SA, le Bois L 'Ev E que,86600 cell L' Evescault, france) and the results are shown in Table 1, wherein, +: >100nM; ++:50-100nM; +++:10-50nM; ++++: < 10nM.
TABLE 1 kinase inhibition data for compounds of the invention
NT: not tested.
Test results show that the compound has good inhibitory activity to PI3K kinase families, and particularly has good inhibitory activity and selectivity to delta subtypes.
Cell viability assay
The cellular activity of the compounds of the invention as inhibitors of PI3K kinase can be assessed by the following assay.
General description of cell assays:
PI3K- α, γ subtype: first compounds were diluted from stock concentrations to 5mM with 100% DMSO. The second step was performed by diluting 5mM of the compound as the first point with 100% DMSO by 4-fold for 10 points. The third step was a 250-fold dilution with serum-free medium, in which case the concentration of DMSO was 0.4%. Then 50. Mu.L of the compound which had been diluted with the culture medium was transferred to a 50. Mu.L cell plate, where the concentration of DMSO was 0.2% and the final concentration of the compound was 10000nM,2500nM,625nM,156.25nM,39.06nM,9.77nM,2.44nM,0.61nM,0.15nM,0.04nM.
PI3K- β, δ subtype: compounds were first diluted from stock concentrations to 1.25mM with 100% DMSO. Second step 1.25mM of compound as first point was diluted 4-fold with 100% DMSO for 10 points. The third step was a dilution of 35.714 in serum-free medium, followed by transfer of 2.5. Mu.L of the compound diluted with medium to a 30. Mu.L cell plate, incubation in an incubator for 1 hour, and addition of 2.5. Mu. Lanti-IgM at a DMSO concentration of 0.2% and a final concentration of 2500nM,625nM,156.25nM,39.06nM,9.77nM,2.44nM,0.61nM,0.15nM,0.04nM,0.01nM.
PI 3K-alpha inhibitory activity detection method
SKOV-3 cells were seeded into cell culture-grade 96-well plates at a density of 60000 cells/50. Mu.L/well in serum-free RPMI-1640, cultured overnight in a 5% CO2 incubator at 37 ℃. Add 50. Mu.L/well of test compound to the cells and incubate them at 37 ℃ for 60 minutes in a 5% CO2 incubator to a final DMSO concentration of 0.2%, aspirate the medium and add 50. Mu.L of 1 Xlysate per well. Shaking for 45 minutes at room temperature. mu.L of lysate was transferred to 384 plates and 4. Mu.L of premixed antibody from the Phospho-AKT (Ser 473) kit from Cisbio was added. Centrifuge at 1000rpm/min for one minute, incubate at 22 ℃ for 4 hours, and read with Spark (665 nm/615 nm).
PI 3K-beta inhibitory activity detection method
786-O cells were seeded at a density of 30000/50. Mu.L/well in 96-well cell culture grade plates in RPMI-1640 medium without serum, cultured overnight in a CO2 incubator at 37 ℃ 5%. Add 50. Mu.L/well of test compound to the cells and incubate them at 37 ℃ for 60 minutes in a 5% CO2 incubator to a final DMSO concentration of 0.2%, aspirate the medium and add 50. Mu.L of 1 Xlysate per well. Shaking for 45 minutes at room temperature. mu.L of lysate was transferred to 384 plates and 4. Mu.L of premixed antibody from the Phospho-AKT (Ser 473) kit from Cisbio was added. Centrifuge at 1000rpm/min for one minute, incubate at 22 ℃ for 4 hours, and read with Envision (665 nm/615 nm).
PI 3K-delta inhibitory activity detection method
Raji cells were cultured in 96-well plates at 30. Mu.L per well, 50,000 cell species in serum-free RPMI-1640. Cells were incubated overnight in 5% CO2 and 37 ℃ incubator. After 18 hours of serum-free starvation, 2.5 μ L of compound (14X) was added to the cells and incubated in an incubator for 60 minutes. Then 2.5. Mu.L (14X, diluted with serum medium) of anti-human IgM (Jackson Immuno Research) was added and placed in an incubator for 30 minutes of stimulation (final concentration 10. Mu.g/mL). Add 11.5. Mu.L of 4 Xlysate to each well. Shake for 45 minutes at room temperature. mu.L of lysate was added to 384 plates and 4. Mu.L of premixed antibody from the Phospho-AKT (Ser 473) kit from Cisbio was added. Centrifuge at 1000rpm/min for one minute, incubate at 22 ℃ for 4 hours, and read with Spark (665 nm/615 nm).
PI 3K-gamma inhibitory activity detection method
RAW264.7 cells were resuspended in serum-free DMEM medium and 60000/45. Mu.L of cell suspension was added per well in a 96-well plate. The cells were incubated overnight in an incubator at 37 ℃ with 5% CO2. After 18 hours of serum-free starvation, 50 μ L of compound was added and incubated in an incubator for 60min. Then 5. Mu.L of 25nM C5a (R & D Systems, diluted in serum medium) was added for stimulation for 5min. Aspirate medium and add 50 μ L of 1x lysate per well. Shake for 45 minutes at room temperature. mu.L of lysate was transferred to 384 plates and 4. Mu.L of premixed antibody from the Phospho-AKT (Ser 473) kit from Cisbio was added. Centrifuge at 1000rpm/min for one minute, 22 ℃ after 4 hours of incubation read with Spark (665 nm/615 nm).
The kinase assay of the present invention was performed by the Biotech company, bonus Biotech (Jiangsu), inc., and the results are shown in Table 2, wherein +: >100nM; ++:50-100nM; +++:10-50nM; ++++: < 10nM.
TABLE 2 cellular Activity data for Compounds of the invention
Test results show that the compound has obvious inhibitory activity on PI3K delta and has very obvious selectivity on the PI3K delta.
Finally, it should be noted that there are other ways of implementing the invention. Accordingly, the embodiments of the present invention will be described by way of illustration, but not limitation to the description of the present invention, and modifications made within the scope of the present invention or equivalents added to the claims are possible. All publications or patents cited herein are incorporated by reference.
Claims (19)
1. A compound having the structure of formula (I):
or a stereoisomer, tautomer, nitroxide, solvate, or pharmaceutically acceptable salt thereof;
wherein the content of the first and second substances,
w is C 3-8 Cycloalkyl radical, C 2-9 Heterocyclic group, C 6-12 Aryl, or C 1-9 A heteroaryl group; wherein W is optionally substituted with 0,1, 2,3 or 4R 7 Substitution;
R a 、R b and R 1 Each independently H, D, F, -CN, -NO 2 、-NH 2 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl, or C 1-6 Cyanoalkyl;
R 2 、R 4 、R 5 and R 6 Each independently is H, D, F, cl, br, I, -OH, -CN, -NO 2 、-NR e R f 、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 2-9 Heterocyclic group, C 3-8 Cycloalkyl, C 6-10 Aryl, or C 1-9 A heteroaryl group; wherein each C is 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 2-9 Heterocyclic group, C 3-8 Cycloalkyl radical, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 0,1, 2,3 or 4 substituents independently selected from H, D, oxo (= O), F, cl, br, I, -OH, -NH 2 、-CN、-NO 2 、C 1-6 Alkyl and C 1-6 A radical substitution of alkoxy;
R 3 is H, D, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, -NR 10a R 10 、-C(＝O)R 9 、-OC(＝O)R 9 、-C(＝O)OR 9a 、-S(＝O) 0- 2 R 9 、-OS(＝O) 1-2 R 9 、-S(＝O) 1-2 OR 9a 、-N(R 10a )C(＝O)R 10 、-C(＝O)NR 10a R 10 、-OC(＝O)NR 10a R 10 、-N(R 10a )S(＝O) 1-2 R 10 、-S(＝O) 1-2 NR 10a R 10 、-N(R 10a )C(＝O)NR 10a R 10 、C 3-8 Cycloalkyl, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-9 Heterocyclic group, C 2-9 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 An alkyl group; wherein R is 3 Optionally substituted by 0,1, 2,3 or 4R 8 Substitution;
R 7 and R 8 At each occurrence, each occurrence is independently H, D, oxo (= O), F, cl, br, I, -OH, -CN, -NO 2 、-NH 2 、-C(＝O)R 9 、-OC(＝O)R 9 、-C(＝O)OR 9a 、-S(＝O) 0-2 R 9 、-OS(＝O) 1-2 R 9 、-S(＝O) 1-2 OR 9a 、-N(R 10a )C(＝O)R 10 、-C(＝O)NR 10a R 10 、-OC(＝O)NR 10a R 10 、-N(R 10a )S(＝O) 1-2 R 10 、-S(＝O) 1-2 NR 10a R 10 、-N(R 10a )C(＝O)NR 10a R 10 、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-9 Heterocyclic group, C 2-9 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 An alkyl group; wherein each of the-C (= O) R 9 、-OC(＝O)R 9 、-C(＝O)OR 9a 、-S(＝O) 0-2 R 9 、-OS(＝O) 1-2 R 9 、-S(＝O) 1-2 OR 9a 、-N(R 10a )C(＝O)R 10 、-C(＝O)NR 10a R 10 、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-9 Heterocyclic group, C 2-9 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl and C 1-9 Heteroaryl C 1-6 Alkyl is independently optionally substituted with 0,1, 2,3 or 4 substituents independently selected from H, D, oxo (= O), F, cl, br, -OH, -NH 2 、-CN、-NO 2 、C 1-6 Alkyl and C 1-6 A radical substitution of alkoxy; and
R e 、R f 、R 9 、R 9a 、R 10 and R 10a Each occurrence, independently, is H, D, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-9 Heterocyclic group, C 2-9 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 An alkyl group; wherein each C is 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-9 Heterocyclic group, C 2-9 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl and C 1-9 Heteroaryl C 1-6 Alkyl is independently optionally substituted with 0,1, 2,3 or 4 substituents independently selected from H, D, oxo (= O), F, cl, br, I, -OH, -NH 2 、-CN、-NO 2 、C 1-6 Alkyl and C 1-6 Alkoxy groups.
2. The compound of claim 1, wherein W is C 3-6 Heterocyclyl, phenyl, or heteroaryl of 5 to 6 atoms; wherein W is optionally substituted with 0,1, 2,3 or 4R 7 And (4) substitution.
3. The method of claim 1Wherein W is phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, thiadiazolyl, or a pharmaceutically acceptable salt thereof,
Wherein Y is 1 Is O, S, or-NH-; and
wherein W is optionally substituted with 0,1, 2,3 or 4R 7 And (4) substitution.
4. The compound of claim 1, wherein R a 、R b And R 1 Each independently is H, D, F, cl, br, I, -OH, -CN, -NO 2 、-NH 2 Methyl, ethyl, methoxy, ethoxy, halomethyl, or haloethyl.
5. The compound of claim 1, wherein R 2 is-NR e R f 、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 1-4 Haloalkyl, cyclopropyl, phenyl, or heteroaryl of 5 to 6 atoms; wherein each of said-NR e R f 、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 1-4 Haloalkyl, cyclopropyl, phenyl and heteroaryl of 5 to 6 atoms are independently optionally substituted with 0,1, 2,3 or 4 substituents independently selected from H, D, oxo (= O), F, cl, br, I, -OH, -NH 2 、-CN、-NO 2 、C 1-4 Alkyl and C 1-4 Alkoxy groups.
6. The compound of claim 1, wherein R 3 Is C 2-4 Alkenyl radical, C 2-4 Alkynyl, -NR 10a R 10 、-C(＝O)NR 10a R 10 、C 3-6 Cycloalkyl radical, C 3-6 Heterocyclyl, phenyl, or heteroaryl of 5 to 6 atoms; wherein R is 3 Optionally substituted by 0,1, 2,3 or 4R is 8 And (4) substitution.
7. The compound of claim 1, wherein R 3 Is vinyl, ethynyl, -C (= O) NH-C 1-3 Alkyl, aryl, heteroaryl, and heteroaryl,
Wherein, the first and the second end of the pipe are connected with each other,
X 1 is O, S, -NH-, - (CH) 2 ) t1 -、-X 2 -(CH 2 ) t1 -, or- (CH) 2 ) t1 -X 2 -(CH 2 ) t2 -；
X 2 At each occurrence, is independently O, S, -NH-, or-CH 2 -；
X 3 Is O, S, or-NH-;
each t1 and t2 is independently 0,1, 2, or 3; and
n is 1,2 or 3;
wherein R is 3 Optionally substituted by 0,1, 2,3 or 4R 8 And (4) substitution.
8. The compound of claim 1, wherein R 2 、R 4 、R 5 And R 6 Each independently of the other is H, D, F, cl, br, I, -OH, -CN, -NO 2 、-NH 2 Methyl, ethyl, isopropyl, methoxy, ethoxy, ethenyl, propenyl, ethynyl, propynyl, halomethyl, haloethyl, phenyl, or cyclopropyl.
9. The compound of claim 1, wherein R 7 And R 8 At each occurrence, each occurrence is individually independentImmediately H, D, oxo (= O), F, cl, br, I, -OH, -CN, -NO 2 、-NH 2 、-C(＝O)R 9 、-OC(＝O)R 9 、-C(＝O)OR 9a 、-S(＝O) 0- 2 R 9 、-OS(＝O) 1-2 R 9 、-S(＝O) 1-2 OR 9a 、-N(R 10a )C(＝O)R 10 、-C(＝O)NR 10a R 10 、-OC(＝O)NR 10a R 10 、-N(R 10a )S(＝O) 1-2 R 10 、-S(＝O) 1-2 NR 10a R 10 、-N(R 10a )C(＝O)NR 10a R 10 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl radical, C 1-4 Aminoalkyl radical, C 1-4 Cyanoalkyl, C 1-4 Alkoxy radical, C 1-4 Alkylamino, cyclopropyl, C 3-6 Heterocyclyl, phenyl, or pyridyl; wherein each of the-C (= O) R 9 、-OC(＝O)R 9 、-C(＝O)OR 9a 、-S(＝O) 0-2 R 9 、-OS(＝O) 1-2 R 9 、-S(＝O) 1-2 OR 9a 、-N(R 10a )C(＝O)R 10 、-C(＝O)NR 10a R 10 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl radical, C 1-4 Aminoalkyl radical, C 1-4 Cyanoalkyl, C 1-4 Alkoxy radical, C 1-4 Alkylamino, cyclopropyl, C 3-6 Heterocyclyl, phenyl and pyridyl are independently optionally substituted with 0,1, 2,3 or 4 substituents independently selected from H, D, oxo (= O), F, cl, br, -OH, -NH 2 、-CN、-NO 2 、C 1-4 Alkyl and C 1-4 Alkoxy groups.
10. The compound of claim 1, wherein R e 、R f 、R 9 、R 9a 、R 10 And R 10a Independently at each occurrence H, D, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyl radical C 1-6 Alkyl radical, C 3-6 Heterocyclic group, C 3-6 Heterocyclyl radical C 1-4 Alkyl radical, C 6-10 Aryl radical, C 6-10 Aryl radical C 1-4 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-4 An alkyl group; wherein each C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyl radical C 1-6 Alkyl radical, C 3-6 Heterocyclic group, C 3-6 Heterocyclyl radical C 1-4 Alkyl radical, C 6-10 Aryl radical, C 6-10 Aryl radical C 1-4 Alkyl radical, C 1-9 Heteroaryl and C 1-9 Heteroaryl C 1-4 Alkyl is independently optionally substituted with 0,1, 2,3 or 4 substituents independently selected from H, D, oxo (= O), F, cl, br, I, -OH, -NH 2 、-CN、-NO 2 、C 1-4 Alkyl and C 1-4 Alkoxy groups.
11. The compound of claim 1, wherein R 7 And R 8 Each occurrence is independently H, D, oxo (= O), F, cl, br, I, -OH, -CN, -NO 2 、-NH 2 、-CH 3 、-CH 2 CH 3 、-CH(CH 3 )CH 3 、-CH 2 CH(OH)CH 3 、-CH 2 CH 2 OH、-CF 3 、-CH 2 CF 3 A cyclopropyl group,
12. The compound of claim 1, which is a compound having one of the following structures:
or a stereoisomer, tautomer, nitroxide, solvate, or pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound of any one of claims 1-12, or a stereoisomer, tautomer, nitroxide, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier, or a combination thereof.
14. The pharmaceutical composition of claim 13, further comprising an additional therapeutic agent.
15. Use of a compound according to any one of claims 1-12 or a pharmaceutical composition according to any one of claims 13-14 in the manufacture of a medicament for preventing, managing, treating, and/or alleviating a disease, disorder, and/or condition associated with PI 3-kinase abnormality, or inhibiting PI 3-kinase activity.
16. The use of claim 15, wherein the PI 3-kinase abnormality associated disease, disorder, and/or condition is selected from respiratory diseases, viral infections, non-viral respiratory infections, allergic diseases, autoimmune diseases, inflammatory diseases, cardiovascular diseases, hematologic malignancies, neurodegenerative diseases, pancreatitis, multi-organ failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury, or pain.
17. The use of claim 15, wherein the PI 3-kinase abnormality associated disease, disorder, and/or condition is selected from asthma, chronic Obstructive Pulmonary Disease (COPD), viral respiratory infection, viral respiratory disease exacerbation, aspergillosis, leishmaniasis, allergic rhinitis, allergic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematological malignancies, neurodegenerative disease, pancreatitis, multi-organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury, pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, posthepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia or central pain.
18. The use of claim 16 or 17, wherein the cancer is selected from acute myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorders, chronic myelogenous leukemia, T-cell acute lymphocytic leukemia, B-cell acute lymphocytic leukemia, non-hodgkin's lymphoma, B-cell lymphoma, solid tumors, or breast cancer.
19. The use of claim 15, wherein the PI 3-kinase is PI3K- δ.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2021109153286 | 2021-08-10 | ||
| CN202110915328 | 2021-08-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115703770A true CN115703770A (en) | 2023-02-17 |
Family
ID=85181490
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210951339.4A Pending CN115703770A (en) | 2021-08-10 | 2022-08-09 | Pyrimidinamine compound and composition and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115703770A (en) |
-
2022
- 2022-08-09 CN CN202210951339.4A patent/CN115703770A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11840513B2 (en) | Substituted nicotinimide inhibitors of BTK for treating cancer | |
| TWI753892B (en) | Pyrrolotriazine compounds as tam inhibitors | |
| CN105732636B (en) | Heteroaromatic compounds and their use in medicine | |
| JP2020114868A (en) | Piperidin-4-yl azetidine derivatives as jak1 inhibitors | |
| JP5976827B2 (en) | Heteroarylpyridone and azapyridone compounds as inhibitors of BTK activity | |
| WO2020108590A1 (en) | Pyrimidine and five-membered nitrogen heterocycle derivative, preparation method therefor, and medical uses thereof | |
| CN113423703A (en) | Nitrogen-containing heterocyclic derivative regulator, and preparation method and application thereof | |
| CN105732637B (en) | Heteroaromatic compounds and their use in medicine | |
| CN108570048B (en) | Substituted heteroaryl compounds, compositions and uses thereof | |
| CN109776522B (en) | Substituted heteroaryl compounds, compositions and uses thereof | |
| CN106432246B (en) | Heteroaromatic compounds and their use in medicine | |
| CN114340634A (en) | Heterocyclic compounds as kinase inhibitors | |
| US10787444B2 (en) | Compounds for the modulation of myc activity | |
| WO2022007921A1 (en) | Triazine compound and composition and use thereof | |
| JP2021503479A (en) | Substituted heteroaryl compound and usage | |
| CN114075221A (en) | Substituted heteroaryl compounds, compositions and uses thereof | |
| CN113683629A (en) | Substituted heteroaryl compounds, compositions and uses thereof | |
| CN115703770A (en) | Pyrimidinamine compound and composition and application thereof | |
| CN114075194A (en) | Substituted heteroaryl compounds, compositions and uses thereof | |
| CN115873000A (en) | Isoquinolone and quinazolinone compounds, and composition and application thereof | |
| CN115850301A (en) | Pyrazolone compound and composition and application thereof | |
| WO2023020486A1 (en) | Rip1 kinase inhibitor compound and composition and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |